ATP11B mediates platinum resistance in ovarian cancer
Myrthala Moreno-Smith, … , Gabriel Lopez-Berestein, Anil K. Sood
Myrthala Moreno-Smith, … , Gabriel Lopez-Berestein, Anil K. Sood
Published May 1, 2013; First published April 15, 2013
Citation Information: J Clin Invest. 2013;123(5):2119-2130. https://doi.org/10.1172/JCI65425.
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Research Article

ATP11B mediates platinum resistance in ovarian cancer

Abstract

Platinum compounds display clinical activity against a wide variety of solid tumors; however, resistance to these agents is a major limitation in cancer therapy. Reduced platinum uptake and increased platinum export are examples of resistance mechanisms that limit the extent of DNA damage. Here, we report the discovery and characterization of the role of ATP11B, a P-type ATPase membrane protein, in cisplatin resistance. We found that ATP11B expression was correlated with higher tumor grade in human ovarian cancer samples and with cisplatin resistance in human ovarian cancer cell lines. ATP11B gene silencing restored the sensitivity of ovarian cancer cell lines to cisplatin in vitro. Combined therapy of cisplatin and ATP11B-targeted siRNA significantly decreased cancer growth in mice bearing ovarian tumors derived from cisplatin-sensitive and -resistant cells. In vitro mechanistic studies on cellular platinum content and cisplatin efflux kinetics indicated that ATP11B enhances the export of cisplatin from cells. The colocalization of ATP11B with fluorescent cisplatin and with vesicular trafficking proteins, such as syntaxin-6 (STX6) and vesicular-associated membrane protein 4 (VAMP4), strongly suggests that ATP11B contributes to secretory vesicular transport of cisplatin from Golgi to plasma membrane. In conclusion, inhibition of ATP11B expression could serve as a therapeutic strategy to overcome cisplatin resistance.

Authors

Myrthala Moreno-Smith, J.B. Halder, Paul S. Meltzer, Tamas A. Gonda, Lingegowda S. Mangala, Rajesha Rupaimoole, Chunhua Lu, Archana S. Nagaraja, Kshipra M. Gharpure, Yu Kang, Cristian Rodriguez-Aguayo, Pablo E. Vivas-Mejia, Behrouz Zand, Rosemarie Schmandt, Hua Wang, Robert R. Langley, Nicholas B. Jennings, Cristina Ivan, Jeremy E. Coffin, Guillermo N. Armaiz, Justin Bottsford-Miller, Sang Bae Kim, Margaret S. Halleck, Mary J.C. Hendrix, William Bornman, Menashe Bar-Eli, Ju-Seog Lee, Zahid H. Siddik, Gabriel Lopez-Berestein, Anil K. Sood

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Figure 2

ATP11B affects cisplatin sensitivity of ovarian cancer cells.

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ATP11B affects cisplatin sensitivity of ovarian cancer cells. (A) A2780-...
(A) A2780-PAR cells transfected with ATP11B construct were plated onto 6-well culture plates and treated with 5 and 7.5 μM cisplatin for 24 hours. Cisplatin-resistant clones were selected by clonogenic assay. Colonies formed were stained with 0.25% Crystal Violet in 20% ethanol for 5 minutes and counted under the light microscope. Among the resistant clones, clone no. 6 showed the highest survival rate. In the presence of 5 μM cisplatin, clone no. 6 yielded 12 times more colonies, compared with A2780-PAR cells and the other clones. ATP11B downregulation increased the sensitivity to cisplatin of (B) A2780-PAR and (C) A2780-CP20 cells. ATP11B silencing decreased the IC50 7 fold and 9 fold in A2780-PAR and A2780-CP20 cells, respectively, compared with A2780-PAR cells transfected with control siRNA (ctr siRNA). Data represent the mean ± SEM. *P < 0.05, **P < 0.01, §P < 0.001, †P < 0.0001, ††P < 0.00001.