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 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 4

ATP11B regulates platinum transport in ovarian cancer cells.

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ATP11B regulates platinum transport in ovarian cancer cells. (A) Platinu...
(A) Platinum (Pt) uptake was significantly decreased in A2780-ATP11B and A2780-CP20 cells compared with that in A2780-EV–transfected cells, whereas (B) DNA adduct formation was significantly increased in the same cell lines. (C) DNA adduct formation after ATP11B silencing resulted in significantly increased DNA adduct formation in both cell lines compared with that in A2780-EV cells. Time kinetics of cisplatin efflux showing the percentage of intracellular remaining platinum content in (D) A2780-PAR, A2780-EV, A2780-ATP11B, and A2780-CP20 cells as well as (E) A2780 control siRNA, A2780 ATP11B siRNA, A2780-CP20 control siRNA, and A2780-CP20 ATP11B siRNA cells after 10 to 30 minutes of incubation without cisplatin (see Methods). Remaining platinum amounts were significantly decreased in A2780-ATP11B–upregulated and A2780-CP20 cells at all time points compared with that in their corresponding control siRNA controls. In contrast, compared with their controls and at all time points, significantly higher platinum contents were determined in ATP11B-silenced A2780-PAR or A2780-CP20 cells. Platinum determinations (duplicates) were performed by flame atomic absorption spectroscopy. Data represent the mean ± SEM from 3 independent experiments. *P < 0.05; **P < 0.01; †P < 0.001.