Anti-tumor effect of CDK inhibitors on CDKN2A-defective squamous cell lung cancer cells

Eun Hui Jeong, Tae Gul Lee, Yun Jung Ko, Seo Yun Kim, Hye Ryoun Kim, Hyunggee Kim, Cheol Hyeon Kim

    Research output: Contribution to journalArticlepeer-review

    26 Citations (Scopus)

    Abstract

    Background: Squamous cell lung cancer (SqCLC) is a distinct histologic subtype of non-small cell lung cancer (NSCLC). Although the discovery of driver mutations and their targeted drugs has remarkably improved the treatment outcomes for lung adenocarcinoma, currently no such molecular target is clinically available for SqCLC. The CDKN2A locus at 9p21 encodes two alternatively spliced proteins, p16INK4a (p16) and p14ARF (p14), which function as cell cycle inhibitors. The Cancer Genome Atlas (TCGA) project revealed that CDKN2A is inactivated in 72% of SqCLC cases. In addition, it was found that CDKN2A mutations are significantly more common in SqCLC than in adenocarcinoma. Down-regulation of p16 and p14 by CDKN2A gene inactivation leads to activation of cyclin-dependent kinases (CDKs), thereby permitting constitutive phosphorylation of Rb and subsequent cell cycle progression. Here, we hypothesized that CDK inhibition may serve as an attractive strategy for the treatment of CDKN2A-defective SqCLC. Methods: We investigated whether the CDK inhibitors flavopiridol and dinaciclib may exhibit antitumor activity in CDKN2A-defective SqCLC cells compared to control cells. The cytotoxic effect of the CDK inhibitors was evaluated using cell viability assays, and the induction of apoptosis was assessed using TUNEL assays and Western blot analyses. Finally, anti-tumor effects of the CDK inhibitors on xenografted cells were investigated in vivo. Results: We found that flavopiridol and dinaciclib induced cytotoxicity by enhancing apoptosis in CDKN2A-defective SqCLC cells, and that epithelial to mesenchymal transition (EMT) decreased and autophagy increased during this process. In addition, we found that autophagy had a cytoprotective role. Conclusion: Our data suggest a potential role of CDK inhibitors in managing CDKN2A-defective SqCLC.

    Original languageEnglish
    Pages (from-to)663-675
    Number of pages13
    JournalCellular Oncology
    Volume41
    Issue number6
    DOIs
    Publication statusPublished - 2018 Dec 1

    Bibliographical note

    Funding Information:
    Acknowledgements This study was supported by a grant from the Korea Institute of Radiological and Medical Sciences (KIRAMS), funded by Ministry of Science and ICT (MSIT), Republic of Korea (50474-2018).

    Funding Information:
    This study was supported by a grant from the Korea Institute of Radiological and Medical Sciences (KIRAMS), funded by Ministry of Science and ICT (MSIT), Republic of Korea (50474-2018). The authors declare that they have no conflict of interest.

    Publisher Copyright:
    © 2018, International Society for Cellular Oncology.

    Keywords

    • CDK inhibitors
    • CDKN2A
    • Dinaciclib
    • Flavopiridol
    • Squamous cell lung cancer

    ASJC Scopus subject areas

    • Molecular Medicine
    • Oncology
    • Cancer Research

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