JNK supports survival in melanoma cells by controlling cell cycle arrest and apoptosis

• Published in: Pigment cell and melanoma research Vol. 21; no. 4; pp. 429 - 438
• Main Authors: Alexaki, Vasileia-Ismini, Javelaud, Delphine, Mauviel, Alain
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2008
• Subjects: Animals; Anthracenes - pharmacology; apoptosis; Apoptosis - drug effects; Apoptosis - physiology; cell cycle; Cell Cycle - drug effects; Cell Cycle - physiology; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell Survival - physiology; growth arrest; Humans; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - physiology; JNK1; JNK2; melanoma; Melanoma - pathology; Mice; Mice, Nude; Mitogen-Activated Protein Kinase 8 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 8 - metabolism; Mitogen-Activated Protein Kinase 8 - physiology; Mitogen-Activated Protein Kinase 9 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 9 - metabolism; Mitogen-Activated Protein Kinase 9 - physiology; p21; p53; RNA, Small Interfering - pharmacology; Tumor Cells, Cultured
• ISSN: 1755-1471; 1755-148X
• DOI: 10.1111/j.1755-148X.2008.00466.x

Summary JNK1/2 proteins belong to the family of stress‐activated protein kinases. They play a complex role in growth regulation, inducing either cell death or growth support. In this report, we provide evidence that, in human melanoma cells, JNK inhibition with the small molecule inhibitor SP600125 induces either predominantly a G2/M arrest or apoptosis depending on the cell line. In 1205Lu cells, JNK inhibition induced cell cycle arrest through p53‐dependent induction of p21Cip1/Waf1 expression, while in WM983B cells, induction of apoptosis by JNK inhibition was accompanied by p53, Bad and Bax induction, not p21Cip1/Waf1. JNK inhibition with the small molecule inhibitor SP600125 slowed growth of all cell lines, although the effect was markedly greater in cells exhibiting high phospho‐ (P‐)JNK1 levels. Specific gene knockdown of JNK1 by means of siRNA oligonucleotides inhibited cell growth only in melanoma cell lines exhibiting high P‐JNK1 levels. siRNAs directed against JNK2 did not reduce cell growth in any of the cell lines tested. Together, our findings demonstrate that JNK, and in particular the JNK1 isoform, support the growth of melanoma cells, by controlling either cell cycle progression or apoptosis depending on the cellular context.