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 3

Therapeutic effectiveness of ATP11B siRNA plus cisplatin in ovarian cancer models.

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Therapeutic effectiveness of ATP11B siRNA plus cisplatin in ovarian canc...
(A) Tumor growth in the A2780-CP20, SKOV3ip1, RMG2, and IGROV-CP20 ovarian cancer models. Each bar represents mean tumor weight + SEM (n = 10). Significantly decreased tumor growth was observed only in mice treated with ATP11B siRNA plus cisplatin. *P < 0.05 (B) Silencing ATP11B reduced tumor proliferation and increased tumor cell apoptosis in ovarian cancer tumors. Tissue sections from A2780-CP20 tumors were immunostained for the detection of proliferating cell nuclear antigen (PCNA) and TUNEL-positive cells to assess tumor proliferation and apoptosis, respectively. Tumor tissues from mice treated with ATP11B siRNA and those treated with ATP11B siRNA plus cisplatin showed significantly lower (*P < 0.001) proliferation and significantly higher (**P < 0.05) apoptotic rates compared with their corresponding controls. Percentages of proliferating and apoptotic cells were calculated in 5 fields for each tissue sample (n = 5). Data represent the mean ± SEM. Original magnification, ×200.