(technical) ATP11B mediates platinum resistance in ovarian cancer

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Introduction

Platinum-based drugs such as cisplatin, carboplatin, and oxaliplatin have a broad range of activity in malignant diseases and are used to treat many types of cancer (1). Since the introduction of cisplatin into clinical trials almost 40 years ago, this drug has had a major impact on the therapeutic management of several tumors, such as those of the ovary, testes, and head and neck (2). Its cytotoxic mode of action is mediated by its interaction with DNA to form adducts, mostly intrastrand crosslink adducts, which activate several signal transduction pathways, including those involving ATR, p53, p73, and MAPK, culminating in the activation of apoptosis (3). Unfortunately, emergence of primary or acquired resistance to platinum agents eventually limits their efficacy (1).
The molecular mechanisms of resistance to cisplatin can be broadly divided into 2 main groups: (a) mechanisms that reduce cisplatin accumulation and, thereby, attenuate DNA damage and (b) mechanisms that inhibit propagation of cisplatin-mediated DNA damage signaling to the apoptotic machinery (3). Earlier studies have documented the development of resistance as a result of increased cisplatin efflux (4, 5). Recently, interest in this resistance mechanism has reemerged as new exporter proteins have been identified. For example, the multidrug resistance-associated gene family includes at least 7 (MRP1–MRP7) ABC-membrane proteins that are involved in the cellular efflux of a variety of drugs (6). However, only MRP2 (also known as cMOAT) seems to be important in cisplatin efflux (7). A second important group of proteins associated with cisplatin resistance comprises ATP7A and ATP7B, 2 copper-membrane transporting P-type ATPases that are overexpressed in cisplatin-resistant tumor cells (8, 9). These copper transporters have been shown to be involved in intracellular cisplatin trafficking and export (10, 11).
Here, we undertook a search for candidate genes that could confer cisplatin resistance in cancer cells. Using genomic analyses, we found that ATP11B gene expression was substantially increased in cisplatin-resistant cells. Moreover, ATP11B enhanced cisplatin efflux and ATP11B silencing restored sensitivity of ovarian cancer cells to cisplatin. These findings identify ATP11B as a potential target for overcoming cisplatin resistance.......