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ERK and PI3K negatively regulate STAT-transcriptional activities in human melanoma cells: implications towards sensitization to apoptosis

Oncogene volume 22, pages 4092–4101 (2003)Cite this article

Abstract

Signal transducers and activators of transcription (STAT) proteins nuclear translocation and transcriptional activity are regulated by diverse protein kinases in response to extracellular stimuli by cytokines, growth factors and stress. Using two melanoma-derived cell lines that exhibit marked differences in basal activities of MAPKs and PI3K-AKT, we studied changes both in STAT activities and in their sensitization to apoptosis. Activating mutations of B-RAF (T1796A) and impaired expression of PTEN are detected in LU1205, but not in FEMX melanoma cells, and are reflected in high basal levels of expression and activities of MAPKs and PI3K-AKT. Treatment with either PD98059 (PD) or LY294002 (LY), the pharmacological inhibitors of MEK-ERK and PI3K, respectively, markedly increased GAS-Luc activity in LU1205, but not in FEMX cells. Tyrosine phosphorylation of STAT3/5 and of JAK2 also increased upon treatment of LU1205 cells with either PD or LY, suggesting that constitutive active MAPK and PI3K signals inhibit tyrosine phosphorylation of JAK/STATs. Treatment of FEMX and LU1205 with PD sensitized the cells to apoptosis, albeit by TNFα and TRAIL death cascades, respectively, indicating that additional yet distinct targets are affected by each signaling pathway. Indeed, the combination of LY and PD treatment synergistically increased the apoptosis of LU1205 and FEMX cells. Overall, whereas PI3K and MAPK downregulate JAK-STAT signaling, additional targets are affected by these kinases and sensitizes melanoma to apoptosis via distinct death cascades.

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Acknowledgements

We thank M Herlyn and O Fodstad for the melanoma cell lines, and J Darnell, Curt Horvath, Andrew Chan, and Roger Davis for constructs. M Krasilnikov has performed these studies at MSSM under the support of grant from Fogarty International. Support by NCI grant (CA51995) to ZR is gratefully acknowledged.

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  1. Mikhail Krasilnikov and Vladimir N Ivanov: Both the authors contributed equally.

Authors and Affiliations

  1. Institute of Carcinogenesis, NN Blochin Cancer Research Center, Moscow, Russia

    Mikhail Krasilnikov

  2. The Ruttenberg Cancer Center, Mount Sinai School of Medicine, 1425 Madison Ave., New York, NY, USA

    Vladimir N Ivanov, Jinali Dong & Ze'ev Ronai

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  1. Mikhail Krasilnikov
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  2. Vladimir N Ivanov
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Correspondence to Ze'ev Ronai.

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Krasilnikov, M., Ivanov, V., Dong, J. et al. ERK and PI3K negatively regulate STAT-transcriptional activities in human melanoma cells: implications towards sensitization to apoptosis. Oncogene 22, 4092–4101 (2003). https://doi.org/10.1038/sj.onc.1206598

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