Downregulation of ATG14 by EGR1-MIR152 sensitizes ovarian cancer cells to cisplatin-induced apoptosis by inhibiting cyto-protective autophagy

Abstract

Cisplatin is commonly used in ovarian cancer treatment by inducing apoptosis in cancer cells as a result of lethal DNA damage. However, the intrinsic and acquired resistance to cisplatin in cancer cells remains a big challenge for improving overall survival. The cyto-protective functions of autophagy in cancer cells have been suggested as a potential mechanism for chemoresistance. Here, we reported MIR152 as a new autophagy-regulating miRNA that plays a role in cisplatin-resistance. We showed that MIR152 expression was dramatically downregulated in the cisplatinresistant cell lines A2780/CP70, SKOV3/DDP compared with their respective parental cells, and in ovarian cancer tissues associated with cisplatin-resistance. Overexpression of MIR152 sensitized cisplatin-resistant ovarian cancer cells by reducing cisplatin-induced autophagy, enhancing cisplatin-induced apoptosis and inhibition of cell proliferation. A mouse subcutaneous xenograft tumor model using A2780/CP70 cells with overexpressing MIR152 was established and displayed decreased tumor growth in response to cisplatin. We also identified that ATG14 is a functional target of MIR152 in regulating autophagy inhibition. Furthermore, we found that EGR1 (early growth response 1) regulated the MIR152 gene at the transcriptional level. Ectopic expression of EGR1 enhanced efficacy of chemotherapy in A2780/CP70 cells. More importantly, these findings were relevant to clinical cases. Both EGR1 and MIR152 expression levels were significantly lower in ovarian cancer tissues with high levels of ERCC1 (excision repair cross-complementation group 1), a marker for cisplatin-resistance. Collectively, these data provide insights into novel mechanisms for acquired cisplatinresistance. Activation of EGR1 and MIR152 may be a useful therapeutic strategy to overcome cisplatin-resistance by preventing cyto-protective autophagy in ovarian cancer.

A microRNA-152 that targets the phosphatase and tensin homolog to inhibit low oxygen induced-apoptosis in human brain microvascular endothelial cells

“…In these reports, overexpression of miRNAs targeting PTEN has been considered a contributing factor for tumor development (Huse et al, 2009). However, as our study indicated, miR-152 is also a potential regulator of PTEN; most previous reports have indicated that miR-152 acts as a tumor suppressor by targeting proteins other than PTEN (Cheng et al, 2014;He et al, 2015;. Therefore, although our data suggest a protective function of miR-152 during hypoxiainduced apoptosis in primary microvascular endothelial cells, the miR-152-PTEN relationship and its effects on the development and progression of cancer requires further investigation.…”

Knockdown of Linc00515 Inhibits Multiple Myeloma Autophagy and Chemoresistance by Upregulating miR-140-5p and Downregulating ATG14

“…Among its related pathways are autophagy pathway and senescence and autophagy in cancer. A recent study has shown that ATG14, a crucial member of ATG gene family, plays a vital role in autophagy processes, [15] which provides protections to cancer cells from the deadly stresses that result from radiation, chemotherapy or other treatments [16]. However, how cancer cells modulate the expression of ATG to prevent cell death caused by radiation and chemotherapy still needs to be discussed.…”

Targeting CD47 and Autophagy Elicited Enhanced Antitumor Effects in Non–Small Cell Lung Cancer

“…Although autophagy acts as a "double-edged sword" in tumorigenesis (19), autophagy acts more as a cytoprotective mechanism in tumor therapy (20)(21)(22). Many anticancer agents, such as imatinib, cisplatin, vismodegib, and asparaginase, can also induce autophagy in tumor cells, whereas inhibition of autophagy significantly enhances the antitumor efficacies of these agents, indicating that a combination of autophagy inhibitors and antitumor agents could be an efficient therapeutic strategy for malignancy (23)(24)(25).…”