CDK5 Functions as a Tumor Promoter in Human Lung Cancer

Zeng, Jie; Xie, Shuanshuan; Liu, Yang; Shen, Changxing; Song, Xiaolian; Zhou, Guowei; Wang, Changhui

doi:10.7150/jca.25967

Cited by 25 publications

(28 citation statements)

References 69 publications

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“…Given that CDK5 is activated and overproduced in lung cancer, 25,26 we speculated that it might play an oncogenic role in lung cancer. To test this hypothesis, we knocked down the expression of CDK5 and found that all 3 SiRNAs and 2 ShRNAs efficiently knocked down CDK5 at the protein level (Fig.…”

Section: Cdk5 Knockdown Suppresses Lung Cancer Progression In Vitro Amentioning

confidence: 99%

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CDK5 Activates Hippo Signaling to Confer Resistance to Radiation Therapy Via Upregulating TAZ in Lung Cancer

Zeng

Liu

Wang

et al. 2020

International Journal of Radiation Oncology*Biology*Physics

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Tumor resistance to radiation therapy is a therapeutic challenge in the treatment of patients with non-small cell lung cancer. Cyclin-dependent kinase 5 (CDK5) has been proposed to participate in cell proliferation, migration and invasion, drug resistance, and immune evasion. However, the functions and regulatory mechanisms of CDK5 in lung cancer radioresistance have not been investigated. Methods and Materials: DNA damage response and repair were measured by neutral comet assay and g-H2AX and Rad51 foci staining. The biological functions of CDK5 in lung cancer radioresistance were investigated with clonogenic survival assays and xenograft tumor models. Small interfering RNAs and short hairpin RNAs were used to knock down CDK5 in A549 and H1299 cells. The effects of CDK5 depletion on the tumorigenic behaviors of lung cancer cells were evaluated in vitro and in vivo. Gene expression was examined by RNA-seq and quantitative real-time polymerase chain reaction. Results: We report that CDK5 depletion impairs lung cancer progression and radioresistance in vitro and in vivo. Mechanistically, we identify TAZ, a component of the Hippo pathway, as a critical downstream effector of CDK5. Loss of CDK5 downregulates TAZ expression and attenuates Hippo signaling activation. Importantly, we provide evidence that TAZ is the major effector mediating the biological functions of CDK5 in lung cancer. Conclusions: These results illustrate that CDK5 activates Hippo signaling via TAZ to participate in tumorigenesis and radioresistance, suggesting that CDK5 may be a promising radiosensitization target for the treatment of lung cancer.

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Section: Cdk5 Knockdown Suppresses Lung Cancer Progression In Vitro Amentioning

confidence: 99%

“…)))P < .001 (n Z 3). Scale bar,25 mm. (E) A549 and H1299 cells transfected with the indicated plasmids and siRNAs were exposed to the indicated radiation doses.…”

mentioning

confidence: 99%

CDK5 Activates Hippo Signaling to Confer Resistance to Radiation Therapy Via Upregulating TAZ in Lung Cancer

Zeng

Liu

Wang

et al. 2020

International Journal of Radiation Oncology*Biology*Physics

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“…CDK5 regulates cell cycle progression, cellular proliferation, and cell migration, and therefore, dysregulation of CDK5 in cellular functions can cause oncogenesis leading to lung and colorectal cancer [46,47]. Notably, when the cancer cells were treated with inhibitors of PPARγ phosphorylation, the cancer cells showed more susceptibility to anti-cancer agents inducing DNA damage responses [53].…”

Section: Discussionmentioning

confidence: 99%

“…To compare the adiponectin production-enhancing activity of CDK5 inhibitors, hBM-MSCs were co-treated with butyrolactone I, Ro-3306, A-674563, AT7519, or roscovitine with IDX when adipogenesis was induced (Figure 2). Because CDK5 inhibitors are cytotoxic or apoptotic against diverse normal or cancer cell lines [46,47], the non-cytotoxic concentrations of Ro-3306, A-674563, AT7519, and roscovitine were chosen for screening their adiponectin production-enhancing activity (Figure 2A). As compared to that of the IDX control, butyrolactone I and roscovitine significantly enhanced adiponectin production, whereas the other CDK5 inhibitors Ro-3306, A-674563, and AT7519 exhibited no significant effects on adiponectin production in hBM-MSCs at non-cytotoxic concentrations (Figure 2A).…”

Section: The Adiponectin Production-enhancing Activity Of Butyrolactomentioning

confidence: 99%

Cyclin-Dependent Kinase 5 Inhibitor Butyrolactone I Elicits a Partial Agonist Activity of Peroxisome Proliferator-Activated Receptor γ

et al. 2020

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Adiponectin is an adipocyte-derived cytokine having an insulin-sensitizing activity. During the phenotypic screening of secondary metabolites derived from the marine fungus Aspergillus terreus, a poly cyclin-dependent kinase (CDK) inhibitor butyrolactone I affecting CDK1 and CDK5 was discovered as a potent adiponectin production-enhancing compound in the adipogenesis model of human bone marrow-derived mesenchymal stem cells (hBM-MSCs). CDK5 inhibitors exhibit insulin-sensitizing activities by suppressing the phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ). However, the adiponectin production-enhancing activities of butyrolactone I have not been correlated with the potency of CDK5 inhibitor activities. In a target identification study, butyrolactone I was found to directly bind to PPARγ. In the crystal structure of the human PPARγ, the ligand-binding domain (LBD) in complex with butyrolactone I interacted with the amino acid residues located in the hydrophobic binding pockets of the PPARγ LBD, which is a typical binding mode of the PPARγ partial agonists. Therefore, the adiponectin production-enhancing effect of butyrolactone I was mediated by its polypharmacological dual modulator activities as both a CDK5 inhibitor and a PPARγ partial agonist.

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“…It is believed that CDK5 promotes self-renewal of malignant brain tumor stem cells such as glioma stem cells [54]. Bioinformatic analyses have demonstrated that increased CDK5 expression importantly supports the migration, proliferation, and metastasis of human lung cancer [55]. One study demonstrated that CDK5 promotes DNA replication due to stress checkpoints, and therefore contributes to the metastasis of breast cancer [41].…”

Section: Cdk5 and Prostate Cancermentioning

confidence: 99%

Future Aspects of CDK5 in Prostate Cancer: From Pathogenesis to Therapeutic Implications

Oner

Lin

Chen

et al. 2019

IJMS

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Cyclin-dependent kinase 5 (CDK5) is a unique member of the cyclin-dependent kinase family. CDK5 is activated by binding with its regulatory proteins, mainly p35, and its activation is essential in the development of the central nervous system (CNS) and neurodegeneration. Recently, it has been reported that CDK5 plays important roles in regulating various biological and pathological processes, including cancer progression. Concerning prostate cancer, the androgen receptor (AR) is majorly involved in tumorigenesis, while CDK5 can phosphorylate AR and promotes the proliferation of prostate cancer cells. Clinical evidence has also shown that the level of CDK5 is associated with the progression of prostate cancer. Interestingly, inhibition of CDK5 prevents prostate cancer cell growth, while drug-triggered CDK5 hyperactivation leads to apoptosis. The blocking of CDK5 activity by its small interfering RNAs (siRNA) or Roscovitine, a pan-CDK inhibitor, reduces the cellular AR protein level and triggers the death of prostate cancer cells. Thus, CDK5 plays a crucial role in the growth of prostate cancer cells, and AR regulation is one of the important pathways. In this review paper, we summarize the significant studies on CDK5-mediated regulation of prostate cancer cells. We propose that the CDK5–p35 complex might be an outstanding candidate as a diagnostic marker and potential target for prostate cancer treatment in the near future.

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CDK5 Functions as a Tumor Promoter in Human Lung Cancer

Cited by 25 publications

References 69 publications

CDK5 Activates Hippo Signaling to Confer Resistance to Radiation Therapy Via Upregulating TAZ in Lung Cancer

CDK5 Activates Hippo Signaling to Confer Resistance to Radiation Therapy Via Upregulating TAZ in Lung Cancer

Cyclin-Dependent Kinase 5 Inhibitor Butyrolactone I Elicits a Partial Agonist Activity of Peroxisome Proliferator-Activated Receptor γ

Future Aspects of CDK5 in Prostate Cancer: From Pathogenesis to Therapeutic Implications

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