Activation of Protein Kinase C by Phorbol 12-Myristate 13-Acetate suppresses the growth of lung cancer cells through KLF6 induction

• Published in: Cancer biology & therapy Vol. 8; no. 9; pp. 801 - 807
• Main Authors: Tahara, Eiji, Kadara, Humam, Lacroix, Ludovic, Lotan, Dafna, Lotan, Reuben
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.05.2009
• Subjects: Binding; Biology; Bioscience; Calcium; Cancer; Carcinoma, Non-Small-Cell Lung - enzymology; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell; Cell Growth Processes - drug effects; Cell Growth Processes - physiology; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - physiology; Cycle; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Activation - drug effects; G1 Phase - drug effects; Humans; Kruppel-Like Factor 6; Kruppel-Like Transcription Factors - biosynthesis; Kruppel-Like Transcription Factors - genetics; Landes; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Organogenesis; Phosphorylation - drug effects; Protein Kinase C - metabolism; Proteins; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins - genetics; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; S Phase - drug effects; Tetradecanoylphorbol Acetate - pharmacology
• ISSN: 1538-4047; 1555-8576
• DOI: 10.4161/cbt.8.9.8186

Phorbol 12-myristate 13-acetate (PMA) modulates cell proliferation and survival by activating several intracellular signaling pathways. Protein kinase C (PKC) plays a key role in PMA-induced growth arrest of non-small cell lung cancer (NSCLC) cells. Kruppel-like transcription factor 6 (KLF6), which is associated with negative control of cell proliferation, is down-regulated in many cancers, including NSCLC. In this study, we found that KLF6 is down- regulated in 17 lung cancer cell lines and in cells representing early stages of lung cancer development. Moreover, PMA induced cell growth arrest through KLF6 induction in H358 NSCLC cells. The increase in KLF6 by PMA was associated with up-regulation of the cyclin- dependent kinase inhibitors (CDKIs) p21WAF1/CIP1 and p27KIP1.  In addition, inhibition of PKC or JNK activation decreased PMA-induced KLF6 induction and activation of PKC alone by Bryostatin-1 and Thymeleatoxin increased KLF6 levels. Moreover, siRNA-mediated knockdown of KLF6 reduced PMA-induced cell growth inhibition concomitantly with decreased expression of both p21WAF1/CIP1 and p27KIP1, and in accordance, over-expression of KLF6 alone up-regulated both CDKIs protein levels. Our results demonstrate the induction of the tumor suppressor KLF6 following PKC activation and its importance for PMA-mediated cancer cell growth arrest.