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Activation of ERK1/2 protects melanoma cells from TRAIL-induced apoptosis by inhibiting Smac/DIABLO release from mitochondria.
Oncogene. 2003 May 15; 22(19):2869-81.O

Abstract

We have previously shown that Smac/DIABLO release from mitochondria appears to be the principal pathway by which TRAIL induces apoptosis of human melanoma. We report that TRAIL-induced release of Smac/DIABLO appears to be downregulated by concomitant signaling through the MEK Erk1/2 kinase pathway and that this inhibits TRAIL-induced apoptosis. Inhibition of Erk1/2 signaling by either the MEK inhibitor U0126 or a dominant-negative mutant of MKK1 markedly sensitized melanoma cells to TRAIL-induced apoptosis. The site in the apoptotic pathway acted on by U0126 appeared to be downstream of caspase-8 and Bid but upstream of caspase-3 in that the levels of proteolytic cleavage of caspase-8 and Bid by TRAIL were similar in cells with or without exposure to U0126. Caspase-3 activation and cleavage of its substrates, PARP, ICAD and XIAP, were however increased by cotreatment with U0126. This was associated with a rapid reduction in mitochondrial transmembrane potential (MMP) and increased release of Smac/DIABLO into the cytosol. Exploration of events leading to the changes in MMP revealed an increased translocation of Bax from the cytosol to mitochondria in the presence of U0126. There was also a delayed decrease in the levels of expression of Mcl-1. Bcl-2 and Bcl-X(L). Over expression of Bcl-2 blocked TRAIL-induced apoptosis in the presence of U0126. Cytochrome c appeared not to play a major role in sensitization of melanoma to TRAIL in that caspase-9 activation was not detected in most of the cell lines. These results suggest that Erk1/2 signaling may protect melanoma cells against TRAIL-induced apoptosis by inhibiting the relocation of Bax from the cytosol to mitochondria and that this may reduce TRAIL-mediated release of Smac/DIABLO and induction of apoptosis.

Authors+Show Affiliations

Immunology and Oncology Unit, Room 443, David Maddison Clinical Sciences Building, Cnr King & Watt Streets, Newcastle, NSW 2300, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12771938

Citation

Zhang, Xu Dong, et al. "Activation of ERK1/2 Protects Melanoma Cells From TRAIL-induced Apoptosis By Inhibiting Smac/DIABLO Release From Mitochondria." Oncogene, vol. 22, no. 19, 2003, pp. 2869-81.
Zhang XD, Borrow JM, Zhang XY, et al. Activation of ERK1/2 protects melanoma cells from TRAIL-induced apoptosis by inhibiting Smac/DIABLO release from mitochondria. Oncogene. 2003;22(19):2869-81.
Zhang, X. D., Borrow, J. M., Zhang, X. Y., Nguyen, T., & Hersey, P. (2003). Activation of ERK1/2 protects melanoma cells from TRAIL-induced apoptosis by inhibiting Smac/DIABLO release from mitochondria. Oncogene, 22(19), 2869-81.
Zhang XD, et al. Activation of ERK1/2 Protects Melanoma Cells From TRAIL-induced Apoptosis By Inhibiting Smac/DIABLO Release From Mitochondria. Oncogene. 2003 May 15;22(19):2869-81. PubMed PMID: 12771938.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of ERK1/2 protects melanoma cells from TRAIL-induced apoptosis by inhibiting Smac/DIABLO release from mitochondria. AU - Zhang,Xu Dong, AU - Borrow,Jodie M, AU - Zhang,Xi Yi, AU - Nguyen,Tam, AU - Hersey,Peter, PY - 2003/5/29/pubmed PY - 2003/6/24/medline PY - 2003/5/29/entrez SP - 2869 EP - 81 JF - Oncogene JO - Oncogene VL - 22 IS - 19 N2 - We have previously shown that Smac/DIABLO release from mitochondria appears to be the principal pathway by which TRAIL induces apoptosis of human melanoma. We report that TRAIL-induced release of Smac/DIABLO appears to be downregulated by concomitant signaling through the MEK Erk1/2 kinase pathway and that this inhibits TRAIL-induced apoptosis. Inhibition of Erk1/2 signaling by either the MEK inhibitor U0126 or a dominant-negative mutant of MKK1 markedly sensitized melanoma cells to TRAIL-induced apoptosis. The site in the apoptotic pathway acted on by U0126 appeared to be downstream of caspase-8 and Bid but upstream of caspase-3 in that the levels of proteolytic cleavage of caspase-8 and Bid by TRAIL were similar in cells with or without exposure to U0126. Caspase-3 activation and cleavage of its substrates, PARP, ICAD and XIAP, were however increased by cotreatment with U0126. This was associated with a rapid reduction in mitochondrial transmembrane potential (MMP) and increased release of Smac/DIABLO into the cytosol. Exploration of events leading to the changes in MMP revealed an increased translocation of Bax from the cytosol to mitochondria in the presence of U0126. There was also a delayed decrease in the levels of expression of Mcl-1. Bcl-2 and Bcl-X(L). Over expression of Bcl-2 blocked TRAIL-induced apoptosis in the presence of U0126. Cytochrome c appeared not to play a major role in sensitization of melanoma to TRAIL in that caspase-9 activation was not detected in most of the cell lines. These results suggest that Erk1/2 signaling may protect melanoma cells against TRAIL-induced apoptosis by inhibiting the relocation of Bax from the cytosol to mitochondria and that this may reduce TRAIL-mediated release of Smac/DIABLO and induction of apoptosis. SN - 0950-9232 UR - https://www.unboundmedicine.com/medline/citation/12771938/Activation_of_ERK1/2_protects_melanoma_cells_from_TRAIL_induced_apoptosis_by_inhibiting_Smac/DIABLO_release_from_mitochondria_ L2 - https://doi.org/10.1038/sj.onc.1206427 DB - PRIME DP - Unbound Medicine ER -