Blocking the ATP11B Gene Restores Ovarian Cancer Cell Sensitivity to Cisplatin

The expression of a protein in the cellular membrane of ovarian cancer cells was found to mediate the development of resistance to platinum-containing chemotherapeutic compounds while blocking this expression restored sensitivity to the drugs.

Platinum compounds, such as cisplatin and carboplatin, are first line therapeutics in the treatment of many solid tumors, as they induce DNA cross-linking that prevents DNA synthesis and repair in rapidly dividing cells. However, the cells frequently develop resistance mechanisms in the form of reduced platinum uptake or increased platinum export that limit the extent of DNA damage.

Using genomic analyses investigators at the University of Texas MD Anderson Cancer Center (Houston, USA) found that ATP11B gene expression was substantially increased in cisplatin-resistant cells. ATP11B is a P-type ATPase, which is phosphorylated in the intermediate state and drives uphill transport of ions across membranes.

The investigators reported in the April 15, 2013, online edition of the Journal of Clinical Investigation 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 (short interfering RNA) 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 enhanced the export of cisplatin from cells.

The investigators concluded that, "These findings identify ATP11B as a potential target for overcoming cisplatin resistance."

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University of Texas MD Anderson Cancer Center