Increased autophagy in EOC re-ascites cells can inhibit cell death and promote drug resistance

Cell Death & Disease, Mar 2018

Yu Liu, Jing Tang, Duanyang Liu, Lei Zhang, Yan He, Jing Li, Lei Gao, Dai Tang, Xiaoming Jin, Dan Kong

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Increased autophagy in EOC re-ascites cells can inhibit cell death and promote drug resistance

Abstract As the major and preferred treatment for ovarian cancer ascites, chemotherapy can reduce or inhibit recurrent ascites (hereafter re-ascites); however, some patients still experience re-ascites. Therefore, this study investigated cases in which epithelial ovarian cancer (EOC) patients experienced re-ascites. In re-ascites cases, CA125, MDR1, LC-3, and Beclin-1 were highly expressed. In addition, CASP-9 and c-CASP-3 expression levels were decreased, and serum CA125 levels (highest 4348 U/ml) were increased compared to chemosensitive cases. The results suggest that high expression levels of Beclin-1 and LC-3, thus increasing the level of autophagy and inhibiting apoptosis in the no-chemotherapy group. In the chemosensitive group, survivin expression was decreased and CASP-9 expression was increased, which led to c-CASP-3 activation and increased tumor cell apoptosis. The results of the cell lines confirm that inhibition of autophagy can increase the sensitivity of ovarian cancer cells to CDDP and promote CDDP-induced cell death. Re-ascites, which appears after chemotherapy, may be associated with drug resistance. In addition, increased autophagy may protect tumor cells from chemotherapeutic drugs, thus inhibiting tumor cell death. Introduction Epithelial ovarian cancer (EOC) is one of the most common gynecological malignancies with a 5-year survival rate lower than 30%; EOC is often accompanied by ascites in late stages1,2. The preferred clinical treatment of ovarian cancer accompanied with ascites is chemotherapy after surgery. The conventional chemotherapy drug is cisplatin, a platinum agent, combined with paclitaxel to inhibit or kill tumor cells. For chemosensitive patients, conventional chemotherapy can inhibit ascites, improve survival quality, and prolong survival time. However, some patients treated with chemotherapy still experience re-ascites, and the recurrence rate is increasing, which is a significant problem in the treatment of advanced ovarian cancer patients3,4. Ovarian cancer ascites is caused by the abdominal spread of tumor cells. The typical characteristics of malignant tumors are fast proliferation and strong invasion. Thus, blood supply frequently cannot meet the growth of the tumor, resulting in a stressed tumor microenvironment that is low in oxygen and deficient in nutrient. Cancer cells survive in such stressful environments by activating various signals, such as the unfolded protein response, changing the metabolic pathway, and undergoing autophagy5,6. The effect of autophagy on tumor energy metabolism provides a theoretical basis for the survival mechanism of tumors under stress conditions. Autophagy is a type of cellular catabolic degradation response to nutrient starvation or metabolic stress7 and is a double-edged sword in tumorigenesis and metastasis. Excessive autophagy can induce autophagic cell death;8 in contrast, autophagy can also play a protective role in tumor cells. Cancers can use autophagy-mediated recycling to maintain mitochondrial function and energy homeostasis to meet the elevated metabolic demand of growth and proliferation, thus resulting in drug resistance9. Autophagy can also affect the biological behavior of the tumor by influencing glucose uptake, glycolysis, oxidative phosphorylation, lipid metabolism, and amino acid metabolism in the tumor cell10,11,12. Various autophagy-related proteins play important roles in the process of autophagy. Microtubule-associated protein 1 light chain 3 (LC-3) is an important gene involved in autophagy. Beclin-1 acts as a tumor suppressor gene to regulate and promote autophagy by enhancing PI3KC3 kinase activity, thereby inhibiting tumor growth13. However, autophagy can also play a pro-tumor role in carcinogenesis by regulating a number of pathways, including Beclin-1, Bcl-2, Class III and I PI3K, mTORC1/C2, and p5314,15. This study investigated the relationships among chemoresistance, autophagy, and apoptosis by evaluating ovarian cancer ascites cases. In addition, we compared the differences between the no-chemotherapy and chemosensitive groups to better understand the processes regulating cell autophagy, which may reveal potential therapeutic targets for drug-resistant tumors. Results Case analysis of EOC patients with re-ascites Among 45 cases in which ascites developed after chemotherapy, 20 involved chemoresistant patients (Fig. S1). Analysis of clinicopathological data found that serum CA125 levels, which tend to return to a normal range after chemotherapy, were increased during re-ascites (as high as 4348 U/ml), and the difference was statistically significant (Fig. 1a, p < 0.001). Meanwhile, 45% (9/20) of tumor tissues were positive for MDR expression. In 25 chemosensitive patients, the serum CA125 level was reduced to a normal level, and ascites were not observed. The qRT-PCR results confirmed that the MDR1 expression level in the re-ascites group was significantly higher than that in the che (...truncated)


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Yu Liu, Jing Tang, Duanyang Liu, Lei Zhang, Yan He, Jing Li, Lei Gao, Dai Tang, Xiaoming Jin, Dan Kong. Increased autophagy in EOC re-ascites cells can inhibit cell death and promote drug resistance, Cell Death & Disease, 2018, Issue: 9, DOI: 10.1038/s41419-018-0449-5