Seino Manabu, Okada Masashi, Sakaki Hirotsugu, Takeda Hiroyuki, Watarai Hikaru, Suzuki Shuhei, Seino Shizuka, Kuramoto Kenta, Ohta Tsuyoshi, Nagase Satoru, Kurachi Hirohisa, Kitanaka Chifumi
Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990‑9585, Japan.
Department of Obstetrics and Gynecology, Yamagata University School of Medicine, Yamagata 990‑9585, Japan.
Oncol Rep. 2016 Jan;35(1):593-601. doi: 10.3892/or.2015.4377. Epub 2015 Nov 2.
Ovarian cancer is the most lethal gynecological malignancy, for which platinum- and taxane-based chemotherapy plays a major role. Chemoresistance of ovarian cancer poses a major obstacle to the successful management of this devastating disease; however, effective measures to overcome platinum and taxane resistance are yet to be established. In the present study, while investigating the mechanism underlying the chemoresistance of ovarian cancer, we found that JNK may have a key role in the resistance of ovarian cancer cells to cisplatin and paclitaxel. Importantly, whereas simultaneous application of a JNK inhibitor and either of the chemotherapeutic agents had contrasting effects for cisplatin (enhanced cytotoxicity) and paclitaxel (decreased cytotoxicity), JNK inhibitor treatment prior to chemotherapeutic agent application invariably enhanced the cytotoxicity of both drugs, suggesting that the basal JNK activity is commonly involved in the chemoresistance of ovarian cancer cells to cisplatin and paclitaxel in contrast to drug‑induced JNK activity which may have different roles for these two drugs. Furthermore, we confirmed using non-transformed human and rodent fibroblasts that sequential application of the JNK inhibitor and the chemotherapeutic agents did not augment their toxicity. Thus, our findings highlight for the first time the possible differential roles of the basal and induced JNK activities in the chemoresistance of ovarian cancer cells and also suggest that time‑staggered JNK inhibition may be a rational and promising strategy to overcome the resistance of ovarian cancer to platinum- and taxane-based chemotherapy.
卵巢癌是最致命的妇科恶性肿瘤，基于铂类和紫杉烷的化疗在其中起着主要作用。卵巢癌的化疗耐药性是成功治疗这种毁灭性疾病的主要障碍；然而，克服铂类和紫杉烷耐药性的有效措施尚未确立。在本研究中，在探究卵巢癌化疗耐药性的潜在机制时，我们发现JNK可能在卵巢癌细胞对顺铂和紫杉醇的耐药性中起关键作用。重要的是，虽然同时应用JNK抑制剂和任何一种化疗药物对顺铂（增强细胞毒性）和紫杉醇（降低细胞毒性）有不同的作用，但在应用化疗药物之前进行JNK抑制剂治疗总是会增强两种药物的细胞毒性，这表明基础JNK活性通常参与卵巢癌细胞对顺铂和紫杉醇的化疗耐药性，与药物诱导的JNK活性形成对比，后者可能对这两种药物有不同的作用。此外，我们使用未转化的人和啮齿动物成纤维细胞证实，顺序应用JNK抑制剂和化疗药物不会增加它们的毒性。因此，我们的发现首次突出了基础JNK活性和诱导JNK活性在卵巢癌细胞化疗耐药性中可能存在的不同作用，并且还表明错开时间的JNK抑制可能是克服卵巢癌对基于铂类和紫杉烷化疗耐药性的一种合理且有前景的策略。
