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Table of Contents
REVIEW ARTICLE
Year : 2019  |  Volume : 62  |  Issue : 6  |  Page : 231-240

Mechanistic insight of cyclin-dependent kinase 5 in modulating lung cancer growth


1 Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
2 Department of Internal Medicine, Division of Chest Medicine, Taichung Veterans General Hospital, Taichung; Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
3 Department of Life Sciences; Program in Translational Medicine and Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
4 Department of Nursing, Asia University; Translational Cell Therapy Center, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan

Date of Submission15-Sep-2019
Date of Acceptance07-Nov-2019
Date of Web Publication29-Nov-2019

Correspondence Address:
Prof. Ho Lin
Department of Life Sciences, National Chung Hsing University, Taichung 40227
Taiwan
Prof. Mei-Chih Chen
Translational Cell Therapy Center, Department of Medical Research, China Medical University Hospital, Taichung 40447
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CJP.CJP_67_19

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  Abstract 

Lung harbors the growth of primary and secondary tumors. Even though numerous factors regulate the complex signal transduction and cytoskeletal remodeling toward the progression of lung cancer, cyclin-dependent kinase 5 (Cdk5), a previously known kinase in the central nervous system, has raised much attention in the recent years. Patients with aberrant Cdk5 expression also lead to poor survival. Cdk5 has already been employed in various cellular processes which shape the fate of cancer. In lung cancer, Cdk5 mainly regulates tumor suppressor genes, carcinogenesis, cytoskeletal remodeling, and immune checkpoints. Inhibiting Cdk5 by using drugs, siRNA or CRISP-Cas9 system has rendered crucial therapeutic advantage in the combat against lung cancer. Thus, the relation of Cdk5 to lung cancer needs to be addressed in detail. In this review, we will discuss various cellular events modulated by Cdk5 and we will go further into their underlying mechanism in lung cancer.

Keywords: CDK5, cytoskeletal remodeling, DNA damage, lung cancer, PD-L1, tumor suppressor


How to cite this article:
Prince GM, Yang TY, Lin H, Chen MC. Mechanistic insight of cyclin-dependent kinase 5 in modulating lung cancer growth. Chin J Physiol 2019;62:231-40

How to cite this URL:
Prince GM, Yang TY, Lin H, Chen MC. Mechanistic insight of cyclin-dependent kinase 5 in modulating lung cancer growth. Chin J Physiol [serial online] 2019 [cited 2019 Dec 8];62:231-40. Available from: http://www.cjphysiology.org/text.asp?2019/62/6/231/272029


  Cyclin-Dependent Kinase 5: an Emerging Player in Lung Adenocarcinoma Top


Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase. It becomes activated on binding to its coactivators p35 and/or p39.[1] Although Cdk5 was regarded as a kinase regulating several neurodegenerative diseases as well as neuronal differentiation, extensive research during the past decades has proved its mysterious role in carcinogenesis.[2],[3],[4],[5],[6],[7],[8] Cdk5 has yet not been reported to regulate cell cycle directly, but it indeed determines the fate of several Cdk5 substrate proteins such as AKT, p53, FAK, deleted in liver cancer 1 (DLC1), apurinic/apyrimidinic endonuclease 1 (APE1), and retinoblastoma (Rb).[4] We also found that Cdk5 can stabilize androgen receptor and signal transducer and activator of transcription factor-3 (STAT3) by phosphorylating at Ser81 and Ser727, respectively, in several malignancies.[9],[10],[11],[12],[13] Besides, Cdk inhibitors such as p21Cip1 and p27Kip1 are also regulated by Cdk5 in cancer.[14],[15] Lung cancer is one of the rising causes of death with increasing incidence and mortality rate, according to the WHO. Lung cancer can be subdivided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC); they can also be categorized to adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. In our recent study, we have found that activated muscarinic acetylcholine receptor 3 triggers downstream epidermal growth factor receptor (EGFR)/Src/focal adhesion kinase (FAK) signaling cascade which leads ultimately to the migration of lung cancer cells. However, tyrosine kinase inhibitors (TKIs) impair this migration of lung cancer cells through interfering with the localization of phospho-Y576-Fak.[16] Notwithstanding the development of TKIs along with the existing chemotherapy and radiotherapy during the past decade has brought great clinical outcomes in treating lung cancer, acquired resistance to TKIs has raised concern to find alternatives in treatment strategies.[17] Lung microenvironment also provides suitable condition for the growth of secondary tumors which makes it a probable destination of metastasis of several malignancies, i.e., breast and colorectal cancer (CRC). Growing evidence support the association of Cdk5 in the progression of lung cancer with a decreased overall survival (OS) rate in Cdk5-positive patients of NSCLC.[18],[19] Bedsides, single-nucleotide polymorphism on the promoter region of Cdk5 has been reported in the Korean population.[20] Altogether, these make Cdk5 a prognostic biomarker in lung cancer.[19],[21] Hence, the activation or repression of Cdk5 in various pathophysiological contexts of cancer has drawn much attention in recent years.[22] In this review, we will discuss recent progresses relating Cdk5 on the tumor growth in the lung and the underlying mechanism [Figure 1].
Figure 1: An overall depiction of the role of cyclin dependent kinase 5 in modulating tumorigenesis in the lung. Cyclin-dependent kinase 5 regulates various cellular processes such as DNA repair mechanism, cytoskeletal remodeling, immune-checkpoints, and tumor suppressors to facilitate the malignancy of cancer through proliferation, invasion, and migration of cancer cell.

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  Physiological Role of Cyclin-Dependent Kinase 5 in Lung Cancer Prognosis Top


There is accumulating evidence that Cdk5 positively regulates the prognosis of lung cancer.[18],[23] Hence, overexpression of Cdk5 is associated with poor overall patient survival. Bioinformatics analysis of several cancer databases has indicated the association between tumor growth and Cdk5.[24] The proliferation of lung cancer cell is stimulated by the overexpression of human basic helix-loop-helix transcription factors such as upstream transcription factor-2 (USF-2) and achaete-scute homolog-1 (hASH1).[23],[25] USF-2 can be phosphorylated by Cdk5 at serine 155 and serine 222 position to promote tumorigenesis and migration in breast and prostate cancer cell line.[26] As breast cancer seldom metastasizes to the lung microenvironment, involvement of Cdk5/USF-2 axis possibly has an important contribution to the tumor formation in the lung.[27]

The migration of cancer to the distant secondary site is always the area of concern in treating cancer. Cancer cells migrate to the secondary organ through epithelial to mesenchymal transition (EMT), in which cancer cell lose their cell-cell adhesion and polarity and acts more like a mesenchymal stem cell. Accumulating evidence suggests that Cdk5 has a regulatory role in EMT as well as metastasis in cancer. Demelash et al. have found the direct association and co-localization of hASH1 and Cdk5 activator protein p35 in migrating SCLC. They propose that ASH1 might be an upstream regulator of Cdk5/p35 which subsequently results in increased migration and invasion. In contrast, silencing hASH1 results in decreased expression of p35 and reduced migration as well as invasion since Cdk5 activity is required for the migration and invasion.[23] In the migration of breast cancer, a complex formed by Cdk5, KIAA0528, and fibroblast growth factor intracellular-binding protein (FIBP) has paramount importance as breast cancers are detected with high expression level of these three proteins. Since breast cancer seldom metastasizes to the lung tissues, this Cdk5 interacting complex might pose some regulatory role in lung cancer migration.[27] The data derived from CRC patients with high expression level of Cdk5 showed decreased OS rate in Kaplan–Meier OS curves. Moreover, Cdk5 has been proved to be an important factor in metastasis of CRC to the lung tissues as the metastatic ability, as well as the number of tumors formed in the lungs, declined followed by the knockdown of Cdk5.[28] In line with this, Liu et al. have reported that Cdk5 has a central role in invasion, migration, and motility of lung cancer cell. Silencing Cdk5, either by using roscovitine or siRNA, reduced the invasion and migration. The tumor mass, formed by A549 cells (NSCLC) transfected with Cdk5 siRNA, also abated.[29]

Epigenetic regulation of Cdk5 activation has a pivotal role in the metastasis potential of carcinomas to the lung. Carcinoma-associated fibroblast (CAF) induces the lung metastasis of breast cancer cells by upregulating HOTAIR (lncRNA HOX transcript antisense RNA). As the CAF secrete high amount of transforming growth factor-beta 1 (TGF-β1), the paracrine signaling by TGF-β1 increased Smad 2/3/4 activation. Interestingly, HOTAIR is a transcriptional target of Smad 2/3/4, as found from the ChIP assay. Hence, the increased expression of HOTAIR contributes to the enhanced EMT and metastasis while Cdk5 being active. For this, one of the inhibitors of Cdk5, Cdk5 regulatory subunit associated protein 1 (CDK5RAP1), and Egr1 is found to have H3K27 me3 on their promoter and further epigenetic silencing of CDK5RAP1 by the recruitment of EZH2 ensues. This TGF-β1/HOTAIR/Cdk5 signaling axis is validated in both patients and mice. Hence, it demands further research on this area in lung cancer.[30]

The involvement of Cdk5 in EMT and metastasis has also been discussed in another work done by Pérez-Morales et al. By the immunohistochemical analysis of clinical specimen from lung cancer, they suggested that p39 and pRb could be used as a biomarker in lung cancer. This correlation between Rb S249 phosphorylation and overexpression of Cdk5 activator protein p39 has become an important factor to determine tumor grades and metastatic potential, respectively.[31] From recent studies, paclitaxel (taxol)-induced cancer metastasis is observed in patients. Although taxol is one of the widely used chemotherapeutic drugs, continual taxol treatment results in taxol-induced metastasis. Cdk5 activation is required for this EMT. Inhibition of Cdk5 using siRNA or roscovitine impaired the metastasis (induced by taxol) of breast cancer to the lung. A small molecular inhibitor, AC1MMYR2 targets Cdk5/miR21 axis to reduce the metastasis events in mice by downregulating mesenchymal markers such as β-catenin and vimentin. This small molecular inhibitor downregulates the p39, one of the Cdk5 activators, along with pFAKSer732 and upregulate CDK5RAP1 which suppress the Cdk5 activation.[32]

In order to grow, survive, and spread, tumor mass requires continuous supply of nutrients and oxygen. They achieve this by sprouting new blood vessels which is termed as angiogenesis. Cdk5 has been associated with endothelial cell survival and migration in cancers.[4] Silencing endothelial Cdk5 reduces the expression of small GTPase Rac1 which ultimately results in decreased angiogenesis in mice.[33] Accordingly, Merk et al. has found that Cdk5 drives angiogenesis through modulating DII4/Notch signaling.[34] In addition to the already acquired resistant to anti-angiogenesis therapy to treat cancer, vasculogenic mimicry (VM) formation by the cancer cells to obtain nutrient independent of endothelial vascularization has coined an unsolved mystery to the scientists. However, in a study published by Zhou et al., the involvement of Cdk5 in forming VM through upregulating FAK/AKT signaling in NSCLC has been reported.[35] These data suggest the regulatory role of Cdk5 in angiogenesis of lung cancer. [Figure 2] summarizes the role and mechanism of Cdk5 in regulating proliferation, angiogenesis, invasion, and migration.
Figure 2: An illustration of various physiological events regulated by cyclin-dependent kinase 5. Transcription factor ASH1 and USF-2 are overexpressed in lung carcinoma. Cyclin-dependent kinase 5 can phosphorylate USF-2 at Ser-155/222 position where ASH1 can upregulate the cyclin dependent kinase 5 co-activator p35 to induce migration and invasion. Silencing cyclin-dependent kinase 5 can impair metastasis of CRC and breast cancer to the lung. Moreover, cyclin-dependent kinase 5 is responsible for VM formation which would pave the way to angiogenesis. CRC: Colorectal cancer, VM: Vasculogenic mimicry, ASH1: Achaete-scute homolog 1, USF-2: Upstream stimulatory factor 2.

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  Tumor Suppressors Regulated by Cyclin-Dependent Kinase 5 in Lung Cancer Top


According to Knudson's two-hit hypothesis model, aberrant expression of tumor suppression genes (TSGs) occurs due to allelic loss, genetic, or epigenetic regulation. However, in an extensive review, Wang et al. suggested a multi-hit hypothesis model for the loss of TSGs. They proposed that not only genetic and epigenetic regulation but also translocation of TSGs between nucleus and cytoplasm, proteasome degradation, and transcriptional regulation might play an essential role in the prognosis of carcinomas along with abnormal expression of TSGs.[36] In cancer, the abnormal expression of tumor suppressors is directly linked to the increased proliferative ability of the cancer cells. In lung cancer, Cdk5 is associated directly or indirectly with several tumor suppressor proteins. In the following paragraphs, we will be discussing some important tumor suppressors and their regulation by Cdk5 in lung cancer.

Mutations in the β isoform of the A subunit serine/threonine protein phosphatase 2A (PP2A), located on human chromosome 11q22-24, is observed in lung adenocarcinoma. PP2A, encoded by the PPP2R1B, is a putative tumor suppressor gene.[37] According to Ruvolo et al., PP2A mutation in lung cancer occurs largely at the scaffold subunit alpha (PPP2R1A) and beta (PPP2R1B), respectively.[38] Among the three subunits of PP2A, A and B work as the regulatory subunits. Since PP2A is a holoenzyme, it becomes activated on binding to its regulatory subunit. The tumor suppressor role of PP2A might diminish if mutations take place in either of Aα or Aβ which would interfere with its binding to B or C subunits.[39] Interestingly, Cdk5 and glycogen synthase kinase-3β (GSK3β) are deregulated due to the knockdown of PP2A subunit PR61/B'δ in mice brain.[40] The crosstalk GSK3β and Cdk5 kinase in Alzheimer's disease by tau hyperphosphorylation have already been established for a long time.[41] As mentioned earlier, Louis et al. also found that in PPR61/B' KO mice nervous system, the microtubule assembly protein tau is hyperphosphorylated along with the downregulation of major tau kinase GSK3β and Cdk5.[40] As aberrant mutations in this tumor suppressor protein PP2A pave the way to the emergence of lung carcinomas and the silencing of PP2A also downregulates Cdk5 in nervous system, this unknown Cdk5, and PP2A crosstalk might be of importance in lung cancer.

Similarly, the major tumor suppressor protein p53 is associated with PP2A since p53 functions are kept in check by PP2A in cervical cancers. Interestingly, Cdk5 phosphorylates p53 at Ser-20/Ser-46 and promotes the recruitment of p53 on p21 or Bax. Resultantly, upregulated p21 and Bax arrest the cell cycle at G2 phase and apoptosis ensues in HeLa cells.[42] Shouse et al. reported that F395C mutation in B56γ-specific PP2A (B56γ-PP2A) alters the p53-dependent tumor suppressor activity of PP2A in lung cancer.[43] In gastric carcinoma, crosstalk between Cdk5 and PP2A has also been reported. Cdk5 activity in gastric carcinoma is somewhat opposite from other carcinomas. Cdk5 knockdown promotes the metastasis of gastric carcinoma, which could be downregulated by silencing PP2A, suggesting a correlation between PP2A and Cdk5.[44] Several studies also report the metastasis of gastric carcinoma to the lung, liver, brain, peritoneum, and bone.[45],[46] In this context, it appears that Cdk5 might also have a regulatory role over PP2A and p53 in lung adenocarcinoma.

Everett et al. reported high expression of PP2A regulatory subunit B56γ in the developmental period in mice. They also suggested a crucial role for B56γ to modulate PP2A expression in lung differentiation.[47] Although, as a tumor suppressor, PP2A regulatory subunit B56γ1 dephosphorylates pERK, ERK activation is found to be upregulated in tumor. Ito et al. found that allelic deletion of B56γ gene correlates to the activation or overexpression of pERK.[48] Correlated to this, another group of researchers reported that the metastatic potential of CRC to the lungs is modulated by Cdk5-ERK5-AP-1 axis.[28] Hence, Cdk5/ERK/PP2A axis possibly play an essential role in the progression of lung adenocarcinoma.

As we have discussed earlier, the major tumor suppressor p53 regulates PP2A. It also regulates the expression of another Cdk inhibitor p21Cip1. Its role in carcinogenesis has proven to be of much importance. In our study published in 2016, we already discovered a hidden role of Cdk5 in regulating nuclear p21Cip1. In lung cancer cell line along with different other cancer cell lines, overexpressed Cdk5 degrades nuclear p21 allowing the promotion of carcinogenesis.[15] In Drosophila, we have discovered the neurodegeneration occurred by the deregulation of Cdk5 kinase by Abl.[49] Interestingly, Shi et al. have found another striking connection between an adaptor protein, Cdk5 and Abl enzyme substrate 1 (Cables1), connecting Cdks (Cdk2, Cdk3, and Cdk5) to the Abl or Wee1 (nonreceptor tyrosine kinases) to phosphorylate Cdks at Tyr-15 site, and p21 in lung cancer as well as other malignancies.[50],[51] They found that Cables1 guards p21Cip1 from proteasome subunit alpha type 3-mediated degradation. Hence, Cables1 upregulates the stability of p21Cip1 on forming a Cables1/p21Cip1 complex in the nucleus and leads to the apoptosis as well as the inhibition of cell growth. Subsequently, the loss of Cables1 may lead to further loss of p21Cip1 protein and enhanced tumorigenesis in lung cancer patients.[51] These studies propose an underlying regulatory mechanism of p21Cip1 by the interplay of Cables1 and Cdk5 in lung cancer.

Another major Cdk inhibitor protein p27kip1 controls one of the Rho families of proteins, RhoA, which has a potential role in cancer metastasis. Hoshino et al. found that the expression of a p27kip1-binding protein, p27RF-Rho, interferes with the p27kip1-mediated regulation of RhoA which ultimately leads to the metastasis of tumor to the lung.[52] Silencing of p27RF-Rho downregulates Cdk5 while upregulating p53 in A549 NSCLC cell line. As a result, the migration and invasion ability of NSCLC cell also decrease.[14] One of the Rho-GTPase activating proteins (Rho-GAP), DLC1 has been found to be downregulated in multiple malignancies including lung cancer. Kim et al. have discovered that the loss of expression of this tumor suppressor protein, DLC1, is due to posttranslational modification.[53] As an anti-oncogenic activity of Cdk5, it targets DLC1 and phosphorylates it at four serine residues at the N-terminal region next to the Rho-GAP domain. This phosphorylation allows binding of focal adhesions (talin, tensin) to it and the Rho-GAP activity increased as the DLC1 activity is downregulated in lung adenocarcinoma.[54] This direct regulation of Cdk5 on the tumor suppressor DLC1 suggests further investigation on specific Cdk5 inhibitors.

One of the major signal transducers having dual role as both tumor suppressor and tumor promoter is TGF-β superfamily. TGF-β regulates various cellular processes such as cell proliferation. Since the roles played by TGF-β in tumorigenesis is discussed broadly by Derynck et al., we will focus on its essential roles and recent developments in lung adenocarcinoma.[55] Through the activities of protease and acidification, the latent TGF-β release the active form of TGF-β, which can bind to one of the transmembrane serine-threonine kinase receptors, namely “type II.” This ignites the signaling cascade once “type I” recognizes and binds to “TGF-β/type II” complex.[55],[56] Loss of expression of TGF-β type II receptors is reported in NSCLC. Kim et al. also found that, in lung cancer, the anti-proliferating effect of TGF-β is linked solely to the kinase activity of “type II” receptors while confirming the binding of “type I” receptors to the “type II” less important in this event.[56] Canonical downstream signaling of TGF-β includes Smad family proteins. In human lung cancer, expression of Smad3 is downregulated by TGF-β signaling. In contrast, stable expression of Smad3 in the presence of TGF-β results in apoptotic cell death.[57] Xu et al. discovered a Cdk5 interacting protein C2-domain interacting phosphoprotein (CDP138). They found that the Cdk5/FIBP/CDC138 complex is responsible of cellular proliferation and migration.[58] CDP138 exerts its role as an upstream regulator of TGF-β/Smad signaling in lung cancer. This Cdk5 interacting protein downregulates growth differentiation factor 15 to impair TGF-β/Smad pathway in lung cancer. Overexpressed CDP138 has been linked to the lymph node metastasis of lung cancer cells when silencing of this Cdk5 interacting proteins has enhanced the radio-sensitivity and decreased the migration rate of lung cancer cell.[59] Since the aberrant TGF-β/Smad expression has been reported in several carcinomas, including lung cancer and Cdk5 interacting protein CDP138 is found to be an upstream regulator of this pathway, this has become an important area to consider in the therapeutic approach of lung adenocarcinoma. These suggest us that Cdk5 is one of the important players in the dysregulation of tumor suppression and that its ability to modulate various tumor suppressor protein makes it a promising target in the treatment of lung cancer as well as other malignancies [Figure 3].
Figure 3: Crosstalk between tumor suppressors and cyclin-dependent kinase 5 in lung cancer. Cyclin-dependent kinase 5 regulates the metastasis of several carcinomas such as colorectal, gastric to the lung as well as lymph node metastasis of lung cancer. Mutations in tumor suppressor PP2A allow the lung tumorigenesis where silencing of B56γ subunit of PP2A leads to the metastasis of colorectal cancer to the lung through ERK5/cyclin-dependent kinase 5/AP-1 axis. Silencing p27RF-Rho upregulates p53 and p27 while downregulating cyclin-dependent kinase 5 and this leads to impaired metastatic potential of NSCLC. Cyclin-dependent kinase 5 also downregulates p21 and DLC1 to aid in carcinogenesis. Similarly, overexpression of cyclin dependent kinase 5 interacting protein CDP138 impairs TGFβ/Smad3 signaling, and lymph node metastasis of lung cancer takes place. GDF15: Growth differentiation factor 15.

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  Dna Damage Response and Cyclin-Dependent Kinase 5 in Lung Cancer Top


Cancer cells tend to overcome the DNA damage checkpoint to continue tumorigenesis. DNA damage response (DDR) plays a vital role in this regard. Especially in lung cancer this DDR pathway significantly contributes to the progression of carcinoma. As in most of the cases where lung cancer occurs due to smoking, the lung tissues are continually being exposed to the carcinogens creating DNA damage. The DDR pathway either repair this damage or this damage happens to be bypassed by mutations in tumor suppressors.[60] The role of Cdk5 in regulating this essential DDR in cancer is already discussed in detail elsewhere.[61] Among the DDR proteins, ataxia-telangiectasia mutated (ATM) and APE1 is regulated by Cdk5.[62],[63]

Lung cancer may appear as adenocarcinoma, large cell carcinoma, or squamous cell carcinoma. One of the malignant types of lung carcinomas, NSCLC, comprise mainly of adenocarcinomas.[64] EGFR-TKI such as gefitinib, erlotinib and iconitib has been commonly used to treat NSCLC. However, continuous EGFR-TKI treatment may lead to acquired TKI resistance. The mutation in PIK3CA gene, loss of Rb, and TP53 are reported in acquired resistant to TKI treatment in lung cancer.[64],[65] Yang et al. found a very strong connection between APE1 and EGFR-TKI resistance in NSCLC. They reported that the lower expression of APE1 correlates to the increased progression-free survival as well as OS rate.[66] APE1, a DNA repair protein, is subjected to phosphorylation by Cdk5 at Thr-233 and Thr-232.[62],[67] Dysregulated APE1 might lead to cell death. Direct interaction of Cdk5 activator protein p35 to APE1 results in the ubiquitination of APE1 in neuronal cell. This event triggers the accumulating DNA damage which eventually leads to neuronal cell death. Downregulation of Cdk5 can rescue this cell death by allowing the base excision repair by APE1.[62] Several transcription factors, such as NFκB, playing vital role in cancer biology is also associated with APE1. In accordance with this, Busso et al. reported that a mimic of the Cdk5 phosphorylation at Thr-233, T233E APE1, leads to the ubiquitination of APE1 in NSCLC line A549 as well as in colon cancer. This ubiquitination is dependent on mdm2 which ultimately leads to cell death and apoptosis. However, in complementation assay using mutant APE1 to elucidate the aftermath of ubiquitination of APE1, they found no significant dysregulation in DNA repair mechanism. However, detail mechanisms of this APE1 regulation by Cdk5 in cancer, especially lung adenocarcinoma, is yet to be discovered.[67]

Interestingly, STAT3 is aberrantly expressed and activated in NSCLC and STAT3 could shape the DDR by regulating essential meiotic structure-specific endonuclease 1.[68],[69] Courapied et al. reported the role of Cdk5 in DDR by regulating STAT3 in cervical cancer.[70] Concomitantly, our findings also confirm the role of Cdk5 in activating STAT3 in prostate cancer.[10] Although the detailed mechanism of Cdk5/STAT3 axis in DDR in lung cancer is yet to be discovered, this signaling pathway may also play a promising role as a therapeutic target.

Kimura et al. found the involvement of Cyclin G1 in DDR in a p53-dependent manner. The mouse embryo fibroblasts lacking the Cyclin G1 gene (Cyclin G-/-) showed increased sensitivity to γ irradiation, and they also reported the engagement of cyclin G1 in G2/M arrest as well as the DNA replication.[71] Cdk5 is a protein associated with cyclin G1, while cyclin G1 is a target gene for P53 transcription factor.[71],[72] It has been already delineated that the overexpression of cyclin G1 rescues cell from radiation-induced G2 arrest leading to cell death by regulating cyclin B1 in lung cancer.[73] Cyclin G1 works as an upstream regulator of Cdk5 kinase. Once Cdk5 is activated it phosphorylate c-myc on Ser-62, which in turn binds to the E-box promoter sequence of cyclin B1 gene.[74] This signaling cascade involving Cdk5 and cyclin G1 in DNA damage repair suggests paramount importance to investigate further their involvement in lung cancer.


  Cyclin-Dependent Kinase 5 in Cytoskeletal Remodeling of Lung Cancer Cells Top


The proteins that shape the cytoskeleton of human cells such as microfilaments or intermediate filaments and microtubules have a pivotal role in determining the fate of cancer or its plasticity. In a review, Fife et al. have already discussed its importance in cancer metastasis.[75] Nevertheless, especially in lung cancer, how Cdk5 plays its role in this, needs to be elucidated. The activation of Cdk5 has implicated its importance in the cytoskeletal remodeling of cancer cell. While Cdk5 supports tumor growth, inhibition of Cdk5 distorts the microfilament formation and disturbs the cytoskeletal remodeling in NSCLC. This inhibition eventually leads to reduced cell proliferation, migration, and invasion.[29]

The reorganization of actin filaments is a prerequisite to the metastasis.[76] Adenylate-cyclase associated protein 1 (CAP1) has been known to be associated with actin filament rearrangement. Overexpressed CAP1 has been found to be responsible for the metastasis of lung cancer through an investigation in the clinical specimen from lung cancer patients.[77] Interestingly, in NSCLC, phosphorylation of CAP1 has been decreased by Cdk5 knockdown followed by reduction in proliferation and migration.[24] Hence, Cdk5 might be an upstream regulator of CAP1. Moreover, Cdk5 allows the recruitment of focal adhesions on tumor suppressor DLC1.[54] The dynamics between actin and focal adhesion proteins are responsible for cell motility.[78] In this, inhibiting Cdk5 reduces the complex formation between Cdk5 and DLC1 as the punctate structures disappear.[54]

Another microtubule assembly protein collapsing response mediator protein (CRMP) has prognostic value as a biomarker in lung cancer, which has already been discussed in detail elsewhere.[79] Here, Cdk5 works as an upstream regulator of one of the proteins of CRMP family, CRMP2. Grant et al. have suggested that Cdk5 can phosphorylate one of the splice variants of CRMP2, CRMP2A, in the nucleus of squamous cell carcinomas of lung cancer.[80] This would result in the further progression of lung cancer. Hence, Cdk5/CRMP2 signaling pathway proposes a novel target in the fight against lung cancer.

On the other hand, Nestin, an intermediate filament protein, is associated with the neuronal stem cell in the central nervous system for a long time.[81],[82] Nestin expression is significantly associated with the differentiation of tumor and lymph node metastasis in lung cancer. Silencing Nestin has disrupted EMT, invasion, and proliferation rate of NSCLC.[81] Several studies have already indicated the involvement of Nestin to induce lung cancer cell proliferation, migration, and invasion.[83],[84] In neuronal precursor cells, Cdk5 can phosphorylate Nestin at Thr-316 and Thr-1495.[85] Although in most of the cases Cdk5 acts as a tumor promoter, a study by Zhang et al. have suggested some different regulation of Cdk5 in tumorigenesis. They found that nuclear Nestin protects tumor cells (lung, prostate, and others) from senescence by stabilizing Lamin A/C, which would encounter Cdk5-dependent proteasomal degradation in a Nestin deficient environment.[86] Thus, the role of Nestin as a biomarker in lung cancer has become more interesting by the discovery of its regulation by Cdk5.[81],[86]


  Cyclin-Dependent Kinase 5 and Programmed Death Ligand 1 in Lung Cancer Top


Immune checkpoints blockage treatment for cancer has gained much attention in recent years. Targeting programmed death protein 1 (PD-1) and its ligand PD-L1 and PD-L2 has come to be a potent target to abate tumor growth. PD-1/programmed death ligand 1 (PDL-1) is a transmembrane protein (CD279) which is associated with various immune cells such as T-cell, B-cell, and NK-cell. In a review, Zerdes et al. have suggested a possible pathway through which PD-1/PDL-1 is activated. According to them, canonical oncogenic pathways such as PI3K/AKT/mTOR, JAK/STAT, or RAS/MEK/ERK pathway may encode for several transcription factors such as STAT3/HIF-1/NFκB/AP-1 which would regulate the expression of PD-L1.[87] However, the PD-L1 regulation among different cancers as well as in different sub-types of the same cancer is not uniform.[88] In NSCLC and SCLC, there are variations in copy number of PD-L1, which may cause the progression of these carcinomas.[89] Certain mutations or alterations in several key molecules such as EGFR, KRAS, ALK contributes to the prognosis of lung cancer. In lung cancer, overexpression of PD-L1 has been linked to tumorigenesis. In a study by Lastwika et al., the expression of PD-L1 in lung cancer occurred through the activation AKT-mTOR pathway.[90] Strikingly, in an investigation on medulloblastoma, Dorand et al. have discovered how Cdk5 allows tumor cells to evade immune-surveillance by permitting the transcriptional activation of PD-L1. In Cdk5 disrupted tumor cells, induced expression of the transcriptional repressors of PD-L1 (IRF-2 and IRF2BP2) inhibits the activation of PD-L1. As a result, CD4+ T cell-mediated tumor rejection follows.[91] Similar to this, Cdk5 attenuation by CRISPR-CAS9 diminished the lung metastasis of triple-negative breast cancer as the PD-L1 expression declined.[92] This selective deletion of Cdk5 may have paramount importance in future lung cancer treatment.


  Therapeutic Approach in Lung Cancer: Cyclin-Dependent Kinase 5 as a Target? Top


The common approach for lung cancer treatment either includes chemotherapeutic drugs or radiotherapy. As several oncogenic drivers are expressed in lung cancers such as EGFR/RAS, so TKIs such as gefitinib, erlotinib, or iconitib have been used as well. Recent studies have demonstrated the significance of Cdk5 in lung cancer treatment. [Table 1] summarizes these recent progresses in the preclinical approach using Cdk5 targeted treatment. In addition to current strategies for Cdk5 targeted therapy, more efforts were invested in synthesizing the compounds which would specifically target Cdk5 and cause its kinase inactivation. The problem of this idea is that the structures of Cdk5 siblings in CDK family are all similar and results in the difficulty to design one specific inhibitor. However, due to the improvement of synthetic biology in recent years, there are signs indicating that it is possible to successfully develop the synthesis of Cdk5 inhibitor in the near future, such as using the structure-based in silico screening.[94] In addition, new Cdk5 inhibitors are also synthesized based on previous Cdk5 inhibitors (or should call pan-Cdk inhibitor), such as Roscovitine.[95] These efforts will be applied into the research and treatment in not only cancer but also neurodegenerative disease in future.
Table 1: Preclinical investigations on cyclin-dependent kinase 5 in lung cancer treatment

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  Conclusion Top


Cancer is a disease of complex regulation. Until recently, we only had rudimentary knowledge on how a Cdk called Cdk5 can determine tumorigenesis. However, many studies have addresses various cellular events in lung cancer regulated by this kinase. A better understanding of the role of this kinase may unfold possible solution to the treatment. Given the evidence, it is clear that Cdk5 works as an oncogenic driver in lung cancer. Thus, inhibiting Cdk5 combining with existing therapy may aid in lung cancer treatment. However, there is evidence that Cdk5 activation in nucleus may lead to tumor senescence in the absence of Nestin. This makes it quite interesting to investigate further into detail since Nestin protects tumor cells from cellular senescence. As in lung cancer, the dire consequences of tumor suppressors directly rely on Cdk5, we suggest that specific small molecular inhibitors or selective delivery systems, i.e., CRISPR/Cas9 to inactivate Cdk5 needs to be implicated.

Acknowledgments

The authors would like to thank Ms. Yu-Hsuan Li for editorial assistance.

This study was supported by the Ministry of Science and Technology, Taiwan (106-2320-B-005-002-MY3/108-2911-I-005-509 to H. L.), the grant of NCHU ENABLE Center (108-16 to H. L.), Taichung Veterans General Hospital/National Chung Hsing University Joint Research Program (TCVGH-NCHU-1097615 to H. L.), and Tungs' Taichung MetroHarbor Hospital (TTMHH-NCHULS107004 to H. L.).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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