Abstract
Chemotherapeutic resistance evolves in about 70 % of ovarian cancer patients and is a major cause of death in this tumor entity. Novel approaches to overcome these therapeutic limitations are therefore highly warranted. A disintegrin and metalloprotease 17 (ADAM17) is highly expressed in ovarian cancer and required for releasing epidermal growth factor receptor (EGFR) ligands like amphiregulin (AREG). This factor has recently been detected in ascites of advanced stage ovarian cancer patients. However, it is not well understood, whether and how ADAM17 might contribute to chemo resistance of ovarian cancer.In this study, we identified ADAM17 as an essential upstream regulator of AREG release under chemotherapeutic treatment in ovarian cancer cell lines and patient derived cells. In the majority of ovarian cancer cells cisplatin treatment resulted in enhanced ADAM17 activity, as shown by an increased shedding of AREG. Moreover, both mRNA and the protein content of AREG were dose-dependently increased by cisplatin exposure. Consequently, cisplatin strongly induced phosphorylation of ADAM17-downstream mediators, the EGFR and extracellular signal-regulated kinases (ERK). Phorbol 12-myristate 13-acetate (PMA), similarly to cisplatin, mediated AREG shedding and membrane fading of surface ADAM17.Inhibition of ADAM17 with either GW280264X or the anti-ADAM17 antibody D1 (A12) as well as silencing of ADAM17 by siRNA selectively reduced AREG release. Thus, ADAM17 inhibition sensitized cancer cells to cisplatin-induced apoptosis, and significantly reduced cell viability.Based on these findings, we propose that targeting of ADAM17 in parallel to chemotherapeutic treatment suppresses survival pathways and potentially diminish evolving secondary chemo resistance mechanisms.
Highlights
Ovarian cancer is the most lethal cancer amongst all gynecological malignancies, with more than 100,000 deaths per year worldwide [1]
AREG was chosen as A disintegrin and metalloprotease 17 (ADAM17) substrate because it was previously identified as one of the most abundant ADAM17 substrates in advanced ovarian cancer [25]
No elevation in ADAM17 content was found in cisplatin-resistant Skov-3 cells (Figure 1 left)
Summary
Ovarian cancer is the most lethal cancer amongst all gynecological malignancies, with more than 100,000 deaths per year worldwide [1]. This circumstance is mainly due to the late stage diagnosis and fast developing chemotherapeutic resistance. Overcoming chemo resistance for decades has been one of the most challenging tasks in successfully treating ovarian cancer [8]. Today, many of these approaches focus on deciphering deregulated signaling pathways in order to reveal novel targets for therapeutic intervention. A critical mediator acting upstream of all these survival pathways is a disintegrin and metalloprotease 17 (ADAM17), which is focus of the present study [9,10,11,12,13]
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