Heterotrimeric stimulatory GTP-binding proteins inhibit cisplatin-induced apoptosis by increasing X-linked inhibitor of apoptosis protein expression in cervical cancer cells.

Abstract

Treatment with cisplatin (cis-dichlorodiammineplatinum (II)) induces DNA double-stranded breaks and apoptosis in many human cancer cells. We have reported that heterotrimeric stimulatory GTP-binding proteins (Gαs) can modulate the apoptotic response of several cancer cells. This study investigated the effect of Gαs on apoptosis triggered by cisplatin and its underlying molecular mechanism in cervical cancer cells. Stable expression of constitutively active Gαs (GαsQL) decreased the release of cytochrome c from the mitochondria to the cytosol and cleavage of caspase-3 and poly(ADP-ribose) polymerases in HeLa cells treated with 30 μM cisplatin, indicating that Gαs inhibited cisplatin-induced apoptosis. Treatment with forskolin also inhibited apoptosis of C33A and CaSKi cervical cancer cells. Expression of GαsQL increased the expression of the X-linked inhibitor of apoptosis protein (XIAP) and partially maintained increased XIAP after cisplatin treatment. Knockdown of XIAP by siRNA augmented apoptosis. Expression of GαsQL increased XIAP mRNA; this increase was inhibited by a protein kinase A inhibitor and cAMP response element (CRE) decoy. A cAMP response element (CRE)-like element at -1396 bp in the XIAP promoter was found to mediate the induction of XIAP by Gαs. In addition, expression of GαsQL protected against the ubiquitin/proteasome-dependent degradation of the XIAP protein. This study shows that Gαs inhibits cisplatin-induced apoptosis by increasing transcription of XIAP and by decreasing degradation of XIAP protein in HeLa cervical cancer cells.

• Authors: Eun-Ah Cho, Jung-Min Oh, So-Young Kim, Yeni Kim, Yong-Sung Juhnn
• Journal: Cancer science (Cancer Sci) Vol. 102 Issue 4 Pg. 837-44 (Apr 2011) ISSN: 1349-7006 [Electronic] England
• PMID: 21255191 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 Japanese Cancer Association.

Chemical References

• Antineoplastic Agents
• RNA, Messenger
• X-Linked Inhibitor of Apoptosis Protein
• XIAP protein, human
• Luciferases
• GTP-Binding Protein alpha Subunits, Gs
• Cisplatin

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cisplatin (pharmacology)
• Female
• GTP-Binding Protein alpha Subunits, Gs (genetics, metabolism)
• Humans
• Luciferases (metabolism)
• RNA, Messenger (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured
• Uterine Cervical Neoplasms (metabolism, pathology)
• X-Linked Inhibitor of Apoptosis Protein (genetics, metabolism)