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Experimental and Molecular Therapeutics

Abstract LB-281: Inhibition of Hedgehog results in altered regulation of c-jun and of ERCC1 in cisplatin-resistant A2780-CP70 human ovarian cancer cells

Kenji Kudo, Elaine Gavin, Shamik Das, Wesley Denny, Martine Jasmin, Lalita Shevde-Samant and Eddie Reed
Kenji Kudo
1University of South Alabama, Mobile, AL.
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Elaine Gavin
1University of South Alabama, Mobile, AL.
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Shamik Das
1University of South Alabama, Mobile, AL.
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Wesley Denny
1University of South Alabama, Mobile, AL.
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Martine Jasmin
1University of South Alabama, Mobile, AL.
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Lalita Shevde-Samant
1University of South Alabama, Mobile, AL.
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Eddie Reed
1University of South Alabama, Mobile, AL.
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DOI: 10.1158/1538-7445.AM10-LB-281 Published April 2010
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Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC

Abstract

Cancer stem cells are presumed to be highly resistant to chemotherapy. Activation of the Hedgehog pathway has been reported as necessary, for the cancer stem cell state. A key gene in the Hedgehog pathway is Gli1. Resistance to platinum compounds is due in part, to up-regulated nucleotide excision repair, NER. ERCC1 is a key marker for NER activity. Transcriptional control of ERCC1 occurs in part, through c-Jun. Upon treatment with cisplatin, cisplatin-resistant A2780-CP70 cells normally up-regulate c-jun and c-fos, which then up-regulate ERCC1 and other NER genes. More specifically, the c-jun Ser63/73 cascade is up-regulated, with up-regulation of activator protein 1 (Reed, JBC 1998). We studied the relationship between Gli1 expression, ERCC1 expression, and cisplatin resistance in the human ovarian cancer cell lines A2780 and A2780-CP70. A2780-CP70 cells are 10-15 fold more resistant to cisplatin than A2780 cells. We used two different probes to modulate the Hedgehog pathway: a) cyclopamine as a pharmacologic inhibitor of the Smoothened; and, b) an anti-Gli1 shRNA to specifically inhibit Gli1. At baseline, cisplatin-resistant cells, expressed > 10-fold more Gli1 protein than cisplatin-sensitive cells. In cisplatin-resistant cells, Gli1 protein was down-regulated in response to cyclopamine, and to anti-Gli1 shRNA. When A2780-CP70 cisplatin-resistant cells are pretreated with cyclopamine, or anti-Gli1 shRNA, the following events occur. The c-jun Thr91/93 cascade is upregulated, which is associated with pro-apoptotic processes. The c-jun Ser63/73 cascade is suppressed. This cascade is associated with pro-growth processes. If cisplatin is given after cyclopamine or anti-Gli1 pretreatment; Gli1 protein is down-regulated; the c-jun Thr91/93 cascade is upregulated; the c-jun Ser63/73 cascade is suppressed; and cells do not up-regulate ERCC1, XPD, or XRCC1. Thus, the normal cisplatin-induced up-regulation of these three genes involved in NER (ERCC1, XPD) and in base excision repair (XRCC1), is suppressed by suppression of the Hedgehog pathway. We conclude that Gli1 and/or other genes involved in the Hedgehog pathway (which is critical for cancer stem cells), may play key roles in the up-regulation of DNA repair genes, specifically in response to DNA damaging agents such as cisplatin.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-281.

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Cancer Research: 70 (8 Supplement)
April 2010
Volume 70, Issue 8 Supplement
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Abstract LB-281: Inhibition of Hedgehog results in altered regulation of c-jun and of ERCC1 in cisplatin-resistant A2780-CP70 human ovarian cancer cells
Kenji Kudo, Elaine Gavin, Shamik Das, Wesley Denny, Martine Jasmin, Lalita Shevde-Samant and Eddie Reed
Cancer Res April 15 2010 (70) (8 Supplement) LB-281; DOI: 10.1158/1538-7445.AM10-LB-281

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Abstract LB-281: Inhibition of Hedgehog results in altered regulation of c-jun and of ERCC1 in cisplatin-resistant A2780-CP70 human ovarian cancer cells
Kenji Kudo, Elaine Gavin, Shamik Das, Wesley Denny, Martine Jasmin, Lalita Shevde-Samant and Eddie Reed
Cancer Res April 15 2010 (70) (8 Supplement) LB-281; DOI: 10.1158/1538-7445.AM10-LB-281
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