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 5

Subcellular localization of ATP11B in cisplatin-sensitive and cisplatin-resistant cells.

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Subcellular localization of ATP11B in cisplatin-sensitive and cisplatin-...
(A) Immunofluorescence staining using antibodies against ATP11B and specific cell markers showed the ATP11B signal mostly in the TGN colocalizing with STX6 (a TGN marker) in A2780-PAR and A2680-CP20 cells (green, STX6; red, ATP11B; blue, nuclei). Higher-magnification images (yellow boxes) from merged images show colocalization of ATP11B and STX6. Color histograms from these areas are included. (B) In both cell lines, FDDP, STX6, and ATP11B colocalized at the TGN at different times of FDDP exposure (15–60 minutes) (green, FDDP; red, ATP11B; blue, STX6). (C) Colocalization of FDDP, VAMP4 (vesicular transport marker), and ATP11B during FDDP exposure (green, FDDP; red, ATP11B; blue, VAMP4) in A2780-PAR and A2780-CP20 cells. Representative confocal images after 0, 15, 30, and 60 minutes of FDDP exposure. (D) Confocal images from A2780-PAR and (E) A2780-CP20 cells in the absence and presence of nonfluorescent cisplatin (0–2 μM), immunostained for the detection of ATP11B/ STX6 and ATP11B/lamin B1 (nuclear marker). In both cell lines colocalization between ATP11B and STX6 was stronger in the presence of cisplatin (asterisks). ATP11B was frequently observed in nuclei from A2780-PAR cells colocalizing with lamin B1 (green, STX6, lamin B1; red, ATP11B; blue, nuclei). Original magnification, ×200; scale bars: 5 μM (A); 10 μM (B–E).