Phosphorylation of caspase-9 at Thr125 directs paclitaxel resistance in ovarian cancer
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Mi Ran Byun1 and Jin Woo Choi1
1Department of Pharmacology, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea
Jin Woo Choi, email: [email protected]
Keywords: ovarian cancer; paclitaxel-induced resistance; caspase-9; CDK1
Received: August 21, 2017 Accepted: November 17, 2017 Published: December 08, 2017
Although paclitaxel is routinely prescribed for the treatment of epithelial ovarian cancer (EOC), paclitaxel resistance is common in EOC and correlates with short survival of patients. A previous pharmacogenomic study revealed the importance of cyclin-dependent kinase 1 (CDK1) activity in drug response. However, a subsequent research showed that the expression level of CDK1 failed to show significant correlation with delayed apoptosis and patient survival. On the contrary, the expression and phosphorylation of capase-9, the downstream target molecule of CDK1, appeared to determine drug resistance. Our results suggest that treatment with the CDK1 inhibitor alsterpaullone reduces phosphorylation of caspase-9. Moreover, caspase-9 phosphorylation was dependent on CDK1 activity and phospho-caspase-9 level directs paclitaxel resistance. This observation was reproducible in xenografted tumors. Thus, the regulation of caspase-9 may be a novel therapeutic strategy to reverse paclitaxel-induced resistance in ovarian cancer cells.
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