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Blocking Mitotic Exit of Ovarian Cancer Cells by Pharmaceutical Inhibition of the Anaphase-Promoting Complex Reduces Chromosomal Instability
Monika Raab*, Mourad Sanhaji*, Shengtao Zhou†, Franz Rödel‡, §, Ahmed El-Balat*, Sven Becker* and Klaus Strebhardt*, §
* Department of Gynecology, Goethe-University, Frankfurt am Main; †State Key Laboratory of Biotherapy, Department of Obstetrics and Gynecology, West China Second Hospital, Sichuan University, Chengdu, 610041, P. R. China;
‡Department of Radiotherapy and Oncology, Goethe University; §German Cancer Consortium (DKTK) / German Cancer Research Center, partner site, Frankfurt a. M.
Paclitaxel is a frontline drug for the treatment of epithelial ovarian cancer (EOC). However, following paclitaxel-platinum based chemotherapy, tumor recurrence occurs in most ovarian cancer patients. Chromosomal instability (CIN) is a hallmark of cancer and represents genetic variation fueling tumor HC030031 to cytotoxic effects of anticancer drugs. In this study, our Kaplan-Meier analysis including 263 ovarian cancer patients (stages I/II) revealed that high Polo-like kinase (PLK) 1 expression correlates with bad prognosis. To evaluate the role of PLK1 as potential cancer target within a combinatorial trial, we induced strong mitotic arrest in ovarian cancer cell lines by synergistically co-targeting microtubules (paclitaxel) and PLK1 (BI6727) followed by pharmaceutical inhibition of the Anaphase-Promoting Complex (APC/C) using proTAME. In short- and long-term experiments, this triple treatment strongly activated apoptosis in cell lines and primary ovarian cells derived from cancer patients. Mechanistically, BI6727/paclitaxel/proTAME stabilize Cyclin B1 and trigger mitotic arrest, which initiates mitochondrial apoptosis by inactivation of antiapoptotic BCL-2 family proteins, followed by activation of caspase-dependent effector pathways. This triple treatment prevented endoreduplication and reduced CIN, two mechanisms that are associated with aggressive tumors and the acquisition of drug resistance. This “two-punch strategy” (strong mitotic arrest followed by blocking mitotic exit) has important implications for developing paclitaxel-based combinatorial treatments in ovarian cancer.
Epithelial ovarian cancer (EOC) is a leading cause of cancer death in women worldwide [1,2]. Microtubule targeting inhibitors like paclitaxel represent one of the most important and promising classes of cancer drugs used in the treatment of ovarian, breast, and lung cancer [3,4]. The Gynecological Cancer Inter Group recommended in 2005 as standard of care for first-line chemotherapy the intravenous adminis-tration of paclitaxel in combination with carboplatin every 3 weeks for 6 cycles [5,6]. Approximately two-thirds of ovarian cancer patients will respond to a therapeutical strategy that starts with surgical debulking and is followed by a paclitaxel/carboplatin-including chemotherapy, but tumor recurrence occurs in most patients at a median of 15 months from initial diagnosis [7–9] often followed by chemoresistance. In addition to its role as first-line agent in a combined therapy, paclitaxel is a promising agent for relapsed platinum-refractory epithelial ovarian
cancer. However, the response to microtubule targeting agents is highly variable, which might interfere with clinical efficiency [10–12]. Importantly, while certain side effects like myelosuppression are manageable, more problematic are the peripheral neuropathies induced by inhibiting microtubule dynamics in nondividing cells .
Abbreviations: CIN, chromosomal instability; APC/C, Anaphase-Promoting Complex; EOC, epithelial ovarian cancer; PLK1, polo-like kinase 1
Address all correspondence to: Prof. Dr. K. Strebhardt, Department of Gynecology, Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main. Received 17 January 2019; Accepted 29 January 2019
© 2019 The Authors. Published by Elsevier Inc. on behalf of Neoplasia Press, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Paclitaxel treatment arrests cells in mitosis due to the presence of a small number of unattached kinetochores , which have not made stable attachments to microtubules, thereby activating the spindle assembly checkpoint (SAC) that delays mitotic progression by inhibiting the ubiquitin ligase activity of the anaphase-promoting complex/cyclosome (APC/C) [15–17]. The APC/C represents a highly complex ubiquitin ligase machinery. At different cell cycle stages the activator proteins CDH1 and CDC20 associate with certain subunits of the APC/C to stimulate APC/C-dependent ubiquitination of substrates and their subsequent proteolysis by the 26S proteasome . Furthermore, the exit from mitosis and the onset of anaphase require CDC20-dependent ubiquitination of APC/C substrates including securin and mitotic cyclins. Cyclin B1 is one of the most important substrates of the APC/C that plays a key role for the timing of the mitotic arrest.