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Down-regulation of Survivin enhances sensitivity to BPR0L075 in human cancer cells via caspase-independent mechanisms

Chun Hei Antonio Cheung¹, Ching-Chuan Kuo¹, Chi-Yen Chang¹, Mohane Selvaraj Coumar², Hsing-Pang Hsieh² & Jang-Yang Chang¹

Correspondence: (Login to view email address)

1. National Institute of Cancer Research, National Health Research Institutes, Taiwan
2. Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Taiwan

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Document Type:

Manuscript

Date:

Received 29 December 2008 09:16 UTC; Posted 29 December 2008

Subjects:

Cancer

Tags:

• apoptosis inducing factor
• tubulin
• survivin
• caspase
• p53
• apoptosis

Abstract:

Background: BPR0L075 [6-methoxy-3-(3’,4’,5’-trimethoxy-benzoyl)-1H-indole] is a novel anti-cancer compound. It inhibits tubulin polymerization and induces mitochondrial-dependent apoptosis in various human cancer cells with different multi-drug resistance (MDR) status. Over-expression of an anti-apoptotic molecule, survivin, causes drug-resistance in various cancers. Survivin inhibits apoptosis by interfering caspase-3 and promotes cell growth by stabilizing microtubule networks. Here, we determined the effects of down-regulation of survivin in BPR0L075 (L075) treatment. Methods: Western blot analysis was used to determine the expression level of survivin in L075-untreated/-treated human oral carcinoma KB and nasopharyngeal carcinoma HONE-1 cancer cells. siRNA was used to down-regulate endogenous survivin. MTT cell viability assay, real-time caspase-3 activity assay and immuno-fluorescence microscopy were used to analyze downstream effects. Results: Survivin expression was up-regulated in both KB and HONE-1 cells in response to L075 treatment. Down-regulation of survivin induced hyper-sensitivity to L075 in KB and re-stored sensitivity to L075 in KB-derived L075-resistant KB-L30 cancer cells. At the molecular level, down-regulation of survivin induced changes in microtubule dynamics in both KB and KB-L30 cells. Surprisingly, down-regulation of survivin did not enhance the activity of caspase-3 in L075 therapy. Instead, down-regulation of survivin induced translocation of the apoptosis-inducing factor (AIF) from cytoplasm to nucleus. Conclusion: Down-regulation of survivin improved drug sensitivity to L075 in both KB and L075-resistant KB-L30 cancer cells, possibly through a tubulin-dependent and caspase-independent mechanism. We suggest that combining BPR0L075 and survivin inhibitor may give better clinical outcome than the use of BPR0L075 monotherapy in future clinical trials.

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This document is licensed to the public under the Creative Commons Attribution 3.0 License

How to cite this document:

Cheung, Chun Hei Antonio, Kuo, Ching-Chuan, Chang, Chi-Yen , Coumar, Mohane Selvaraj, Hsieh, Hsing-Pang, and Chang, Jang-Yang. Down-regulation of Survivin enhances sensitivity to BPR0L075 in human cancer cells via caspase-independent mechanisms. Available from Nature Precedings <http://hdl.handle.net/10101/npre.2008.2729.1> (2008)

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