Resistance is futile


Platinum compounds, such as cisplatin and carboplatin, induce DNA cross-linking, prohibiting DNA synthesis and repair in rapidly dividing cells. They are first line therapeutics in the treatment of many solid tumors, but cancer cells frequently develop resistance to these drugs. Mechanisms of resistance typically include reduced platinum uptake and increased platinum export. Myrthala Moreno-Smith and colleagues identified a membrane protein, ATP11B, that mediates cisplatin resistance in ovarian cancer cells. They 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. Further, ATP11B gene silencing restored the sensitivity of ovarian cancer cell lines to cisplatin in vitro and combined cisplatin/ATP11B shRNA therapy reduced ovarian tumor growth in mice. The accompanying image shows ATP11B (red) and Lamin B (green) expression in A2780 ovarian cancer cells (the nuclei are blue) treated with cisplatin, demonstrating that ATP11B moves from the nucleus to the cytoplasm upon exposure to cisplatin. These findings suggest that ATP11B could serve as a therapeutic target to overcome cisplatin resistance.

Published April 15, 2013, by Jillian Hurst

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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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