Down The Molecular Chaperone Mortalin Expression And Reverse Ovarian Cancer Resistance-related Research

Heat shock proteins (HSPs) are ubiquitous evolutionary conserved proteins. HSPs are involved in gene expression regulation, DNA replication, signal transduction, differentiation, apoptosis and so on. Mortalin, as a member of the HSP70 family, performs several functions, including stress responses, intracellular transport, mitochondrial import, control of cellular proliferation and differentiation, et al.Mortalin is overexpressed in various human malignancies, but we know little about the relationship between Mortalin and ovarian cancner. In this study, the tissue microarrays including 183 ovarian cancer cases showed that Mortalin is overexpressed in ovarian cancer, which has relationship with advanced stage and serous carcinoma. Considering serous ovarian cancer is more easily drug-resistant compared with mucinous ovarian cancer and the sensitivity of ovarian cancer to chemotherapeutics depends on the differentiation of cancer cells which means the lower differentiation, the more sensitivity to chemotherapeutics. We speculate that the overexpression of Mortalin may be related with drug-resistance.The expression of Mortalin in ovarian cancer cell lines was further confirmed by Real-time PCR and immunoblots. Higher levels of Mortalin mRNA and protein were detected in cisplatin-resistant ovarian cancer cells compared with cisplatin-sensitive ovarian cancer cells. Here, we show that silencing of Mortalin in cisplatin-resistant ovarian cancer cells dramatically inhibits cells proliferation and sensitizes cells to cisplatin-induced apoptosis. Colony formation assays and invasion assays demonstrated that silencing of Mortalin effectively decreases the motility rate and invasion potential of cells. In vivo, tumor growth was inhibited when accompanied with the silencing of Mortalin in A2780/cis cells.P53, as an anti-oncogene and interactors with Bax, Mortalin, plays a significant effect in promoting and maintaining tumor growth. Cisplatin-induced apoptosis in ovarian cancer cells is p53 dependent. Abnormal p53 regulation can result in cisplatin-resistance in cancer. The immunofluorescence and immunoblots result showed that abrogation of Mortalin induction in cisplatin-resistant ovarian cancer cells reactivated p53 and enhanced its nuclear translocation, which plays an effective role in enhancing the sensitivity of ovarian cancer cells to cisplatin.The PI3K/AKT and MEK/ERK pathways are two important survival pathways. Akt and Erkl/2 are two important molecules which regulate the downstreams of signal pathways and exert key roles in the progression and metastasis of various human cancers. Immunoblots result indicated that silencing of Mortalin effectively decreased the levels of Akt and Erkl/2 phosphorylation. Akt phosphorylation was still inhibited and Erkl/2 was actived when treated with cisplatin. Silencing of Mortalin in A2780/cis cells also affected the P38/MAPK pathway. The activation of p38 was greatly enhanced when treated with cisplatin compared with A2780/cis which can more efficiently regulate apoptosis.In conclusion, it has relationship between Mortalin and drug-resistant ovarian cancer. Silencing of Mortalin effectively decreased the motility rate and invasion potential of cells. Moreover, abrogation of Mortalin induction in cisplatin-resistant ovarian cancer cells reactivated p53 and enhanced its nuclear translocation, reduced Akt phosphorylation,and potentiated p38 and Erkl/2 phosphorylation. We conclude that Mortalin supports resistance to cytotoxicity in cancer cells and highlight it as a candidate target to improve treatment of drug-resistant ovarian cancer.