Silencing of BAG3 promotes the sensitivity of ovarian cancer cells to cisplatin via inhibition of autophagy

Abstract

Abstract. Ovarian cancer is the most lethal disease among all gynecological malignancies. Interval cytoreductive surgery and cisplatin-based chemotherapy are the recommended therapeutic strategies. However, acquired resistance to cisplatin remains a big challenge for the overall survival and prognosis in ovarian cancer. Complicated molecular mechanisms are involved in the process. At present, increasing evidence indicates that autophagy plays an important role in the prosurvival and resistance against chemotherapy. In the present study, as a novel autophagy regulator, BCL2-associated athanogene 3 (BAG3) was investigated to study its role in cisplatin sensitivity in epithelial ovarian cancer. However, whether BAG3 participates in cisplatin sensitivity by inducing autophagy and the underlying mechanism in ovarian cancer cells remain to be clarified. Through the use of quantitative real-time PCR, western blot analysis, CCK-8 and immunofluorescence assays our data revealed that cisplatin-induced autophagy protected ovarian cancer cells from the toxicity of the drug and that this process was regulated by BAG3. Silencing of BAG3 increased cisplatininduced apoptosis. The results also revealed BAG3 as a potential therapeutic target which enhanced the efficacy of cisplatin in ovarian cancer.

Silencing of BAG3 inhibits the epithelial-mesenchymal transition in human cervical cancer

“…The present study identified that BAG3 was highly expressed in CC tissues and cell lines. Consistently, previous reports also demonstrated that BAG3 was over-expressed in colorectal and prostate cancer [ 10 – 13 ]. These findings indicate that BAG3 acts as an oncogene, which was responsible for the progression of cervical cancer.…”

“…BAG3, a member of six BAG families, contains a conserved domain, and interacts with Hsp-70 [ 6 – 9 ]. It has been reported that BAG3 is highly expressed in many kinds of primary tumors, including ovarian cancer, and glioblastoma [ 10 – 13 ]. In addition, BAG3 is able to modulate some tumor biology processes, involving cell apoptosis, growth, cytoskeleton organization, and differentiation [ 14 , 15 ].…”

The multifaceted role of autophagy in cancer and the microenvironment

“…Correspondingly, resistance to various types of therapy is characterized by enhanced basal levels of autophagy, as defined by increased conversion of LC3‐I to LC3‐II, increased numbers of LC3B puncta per cell, upregulated numbers of autophagolysosomes, and degradation of p62 . For example, cisplatin‐resistant clones of ovarian cancer cell lines as well as an oral squamous cell carcinoma cell line were characterized by enhanced levels of autophagic flux . In radiotherapy‐resistant breast cancer cells, ionizing radiation also elevated basal autophagy levels, indicating a protective effect of autophagy against treatment .…”

Autophagy in Cancer Cell Death

“…For pancreatic cancer, it has been shown that primary tumors and cell lines exhibit increased autophagy, while autophagy inhibition (genetic and pharmacological) results in increased reactive oxygen species (ROS) formation and DNA damage, while treatment of tumor-bearing mice with the autophagic flux-inhibitor chloroquine (CQ) improved overall survival [40]. In another study Qiu et al showed that autophagy induced by cisplatin protected ovarian cancer cells [41], while DeVorkin et al could, in fact, show that cancer cells of clear-cell ovarian cancer depend on autophagy for their survival [42]. From a mechanistic perspective, it should, however, be noted that CQ is not a highly selective inhibitor of autophagy.…”