Rubus coreanus Miquel extract causes apoptosis of doxorubicin-resistant NCI/ADR-RES ovarian cancer cells via JNK phosphorylation
Rubus coreanus Miquel extract causes apoptosis of doxorubicin-resistant NCI/ADR-RES ovarian cancer cells via JNK phosphorylation
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DOI：
10.3892/mmr.2016.4996
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发表时间：
2016-05-01
影响因子：
3.4
通讯作者：
Ko, Seong-Gyu
中科院分区：
文献类型：
--
作者：
Kim, Min Kyoung;Choi, Hyeong Sim;Ko, Seong-Gyu
癌细胞可以在化疗后获得抗癌、耐药表型，这与癌症的恶性程度和患者的存活率密切相关。因此，确定治疗化疗耐药癌细胞的方案是当务之急。悬钩子(Rubus coreanus Miquel，RCM)长期以来一直被用作食物来源。此外，据报道，RCM对某些疾病具有有效的功能，包括癌症和炎症。在本研究中，RCM提取物通过磷酸化c-Jun氨基末端激酶(JNK)而导致耐阿霉素的NCI/ADR-RES卵巢癌细胞的凋亡。RCM介导的细胞活力下降与阿霉素无协同作用。此外，RCM中发现的植物化学物质--鞣花酸和槲皮素也能引起NCI/ADR-RES细胞的凋亡。在随后对RCM改变的信号通路的研究中，RCM提取物、鞣花酸和槲皮素被发现共同诱导JNK和AKT的磷酸化。此外，SP600125对JNK的抑制作用可抑制RCM提取物、鞣花酸和槲皮素诱导的细胞死亡，且JNK的抑制作用可使细胞由凋亡转为坏死。JNK抑制也降低了RCM提取物、鞣花酸和槲皮素诱导的AKT的磷酸化，提示在RCM、鞣花酸或槲皮素诱导的细胞死亡中，JNK的磷酸化是AKT磷酸化所必需的。因此，本研究得出结论，RCM通过JNK磷酸化导致耐阿霉素的NCI/ADR-res卵巢癌细胞的凋亡，提示RCM可能对化疗耐药的肿瘤细胞有治疗作用。
Cancer cells can acquire an anticancer, drug-resistant phenotype following chemotherapy, which is tightly linked to cancer malignancy and patient survival rates. Therefore, the identification of options to treat chemotherapy-resistant cancer cells is an urgent requirement. Rubus coreanus Miquel (RCM) has long been used as a source of food. In addition, it has been reported that RCM has effective functions against particular diseases, including cancer and inflammation. In the present study, it was demonstrated that RCM extract caused the apoptotic cell death of doxorubicin-resistant NCI/ADR-RES ovarian cancer cells by phosphorylating c-Jun N-terminal kinase (JNK). The RCM-mediated reduction of cell viability showed no synergism with doxorubicin. In addition, ellagic acid and quercetin, which are phytochemicals found in RCM, also caused apoptosis of the NCI/ADR-RES cells. In subsequent investigations of the RCM-altered signaling pathway, RCM extract, ellagic acid and quercetin were found to commonly induce the phosphorylation of JNK and AKT. Additionally, the inhibition of JNK with SP600125 repressed the apoptotic cell death induced by RCM extract, ellagic acid and quercetin, and the inhibition of JNK appeared to switch apoptosis to necrosis. JNK inhibition also reduced the phosphorylation of AKT, which was induced by RCM extract, ellagic acid and quercetin, suggesting that the phosphorylation of JNK is required for AKT phosphorylation in RCM-, ellagic acid- or quercetin-induced apoptotic cell death. Therefore, the data obtained in the present study led to the conclusion that RCM caused apoptosis of doxorubicin-resistant NCI/ADR-RES ovarian cancer cells via JNK phosphorylation, and suggested that RCM may be effective in the treatment of chemotherapy-resistant cancer cells.