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 journalArticle

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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
JournalCellular Oncology
DOIs
Publication statusAccepted/In press - 2018 Jan 1

Fingerprint

Squamous Cell Neoplasms
Cyclin-Dependent Kinases
Lung Neoplasms
alvocidib
Neoplasms
Tumor Suppressor Protein p14ARF
Autophagy
Cell Cycle
Cyclin-Dependent Kinase Inhibitor p16
Apoptosis
p16 Genes
Mutation
Epithelial-Mesenchymal Transition
Atlases
In Situ Nick-End Labeling
Gene Silencing
Non-Small Cell Lung Carcinoma
Cell Survival
Adenocarcinoma
Down-Regulation

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

Cite this

Anti-tumor effect of CDK inhibitors on CDKN2A-defective squamous cell lung cancer cells. / Jeong, Eun Hui; Lee, Tae Gul; Ko, Yun Jung; Kim, Seo Yun; Kim, Hye Ryoun; Kim, Hyunggee; Kim, Cheol Hyeon.

In: Cellular Oncology, 01.01.2018.

Research output: Contribution to journalArticle

Jeong, Eun Hui ; Lee, Tae Gul ; Ko, Yun Jung ; Kim, Seo Yun ; Kim, Hye Ryoun ; Kim, Hyunggee ; Kim, Cheol Hyeon. / Anti-tumor effect of CDK inhibitors on CDKN2A-defective squamous cell lung cancer cells. In: Cellular Oncology. 2018.
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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.",
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T1 - Anti-tumor effect of CDK inhibitors on CDKN2A-defective squamous cell lung cancer cells

AU - Jeong, Eun Hui

AU - Lee, Tae Gul

AU - Ko, Yun Jung

AU - Kim, Seo Yun

AU - Kim, Hye Ryoun

AU - Kim, Hyunggee

AU - Kim, Cheol Hyeon

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - CDK inhibitors

KW - CDKN2A

KW - Dinaciclib

KW - Flavopiridol

KW - Squamous cell lung cancer

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