This Article Full Text Full Text (PDF) All Versions of this Article: 1078-0432.CCR-07-0665v1 13/16/4934    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, Y. F. Articles by Hersey, P. Search for Related Content PubMed PubMed Citation Articles by Wang, Y. F. Articles by Hersey, P.

Apoptosis Induction in Human Melanoma Cells by Inhibition of MEK Is Caspase-Independent and Mediated by the Bcl-2 Family Members PUMA, Bim, and Mcl-1

Authors' Affiliation: Immunology and Oncology Unit, Room 443, David Maddison Clinical Sciences Building, Cnr. King and Watt Streets, Newcastle, NSW, Australia

Requests for reprints: Peter Hersey, Room 443, David Maddison Clinical Sciences Building, Cnr. King and Watt Streets, Newcastle, NSW 2300, Australia. Phone: 61-2-49-236828; Fax: 61-2-49-236184; E-mail: Peter.Hersey{at}newcastle.edu.au.

Purpose: Given that inhibitors of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) are being introduced into treatment for melanoma, the present study was carried out to better understand the mechanism by which they may induce apoptosis of melanoma cells.

Experimental Design: A panel of human melanoma cell lines and fresh melanoma isolates was assessed for their sensitivity to apoptosis induced by the MEK inhibitor U0126. The apoptotic pathways and regulatory mechanisms involved were examined by use of the inhibitor and small interfering RNA (siRNA) techniques.

Results: Inhibition of MEK induced apoptosis in the majority of melanoma cell lines through a mitochondrial pathway that was associated with the activation of Bax and Bak, release of mitochondrial apoptogenic proteins, and activation of caspase-3. However, apoptosis was independent of caspases and instead was associated with mitochondrial release of AIF as shown by the inhibition of apoptosis when AIF was knocked down by siRNA. Inhibition of MEK resulted in the up-regulation of the BH3-only proteins PUMA and Bim and down-regulation of the antiapoptotic protein Mcl-1. These changes were critical for the induction of apoptosis by U0126 as siRNA knockdown of PUMA or Bim inhibited apoptosis, whereas siRNA knockdown of Mcl-1 increased apoptosis particularly in the apoptosis-resistant cell lines.

Conclusions: Apoptosis of melanoma cells induced by the inhibition of the MEK/ERK pathway is mediated by the up-regulation/activation of PUMA and Bim and down-regulation of Mcl-1. Release of AIF rather than the activation of caspases seems to be the mediator of apoptosis. Our results suggest that cotargeting Mcl-1 and the MEK/ERK pathway may further improve treatment results in melanoma.

This article has been cited by other articles:

				M. W. VanBrocklin, M. Verhaegen, M. S. Soengas, and S. L. Holmen Mitogen-Activated Protein Kinase Inhibition Induces Translocation of Bmf to Promote Apoptosis in Melanoma Cancer Res., March 1, 2009; 69(5): 1985 - 1994. [Abstract] [Full Text] [PDF]

				M. A. Park, G. Zhang, C. Mitchell, M. Rahmani, H. Hamed, M. P. Hagan, A. Yacoub, D. T. Curiel, P. B. Fisher, S. Grant, et al. Mitogen-activated protein kinase kinase 1/2 inhibitors and 17-allylamino-17-demethoxygeldanamycin synergize to kill human gastrointestinal tumor cells in vitro via suppression of c-FLIP-s levels and activation of CD95 Mol. Cancer Ther., September 1, 2008; 7(9): 2633 - 2648. [Abstract] [Full Text] [PDF]

				G. Zhang, M. A. Park, C. Mitchell, H. Hamed, M. Rahmani, A. P. Martin, D. T. Curiel, A. Yacoub, M. Graf, R. Lee, et al. Vorinostat and Sorafenib Synergistically Kill Tumor Cells via FLIP Suppression and CD95 Activation Clin. Cancer Res., September 1, 2008; 14(17): 5385 - 5399. [Abstract] [Full Text] [PDF]

				C. C. Jiang, K. Lucas, K. A. Avery-Kiejda, M. Wade, C. E. deBock, R. F. Thorne, J. Allen, P. Hersey, and X. D. Zhang Up-regulation of Mcl-1 Is Critical for Survival of Human Melanoma Cells upon Endoplasmic Reticulum Stress Cancer Res., August 15, 2008; 68(16): 6708 - 6717. [Abstract] [Full Text] [PDF]

				P. Javvadi, A. T. Segan, S. W. Tuttle, and C. Koumenis The Chemopreventive Agent Curcumin Is a Potent Radiosensitizer of Human Cervical Tumor Cells via Increased Reactive Oxygen Species Production and Overactivation of the Mitogen-Activated Protein Kinase Pathway Mol. Pharmacol., May 1, 2008; 73(5): 1491 - 1501. [Abstract] [Full Text] [PDF]

				V. Benedetti, P. Perego, G. Luca Beretta, E. Corna, S. Tinelli, S. C. Righetti, R. Leone, P. Apostoli, C. Lanzi, and F. Zunino Modulation of survival pathways in ovarian carcinoma cell lines resistant to platinum compounds Mol. Cancer Ther., March 1, 2008; 7(3): 679 - 687. [Abstract] [Full Text] [PDF]