Abstract
Chemoresistance has been the biggest obstacle in ovarian cancer treatment, and STAT3 may play an important role in chemoresistance of multiple cancers, but the underlying mechanism of STAT3 in ovarian cancer chemoresistance has long been truly illusive, particularly in association with p53 and RAS signaling. In this study, by using wild type, constitutive active, and dominant negative STAT3 constructs, wild-type p53, and RAS-mutant V12, we performed a series of in vitro and in vivo experiments by gene overexpression, drug treatment, and animal assays. We found that phosphorylation of STAT3 Y705 but not S727 promoted cancer cell EMT and metastasis through the Slug-mediated regulation of E-cadherin and Vimentin. The phosphorylation of STAT3 at Y705 also activated the MAPK and PI3K/AKT signaling to inhibit the ERS-mediated autophagy through down-regulation of pPERK, pelf2α, ATF6α, and IRE1α, which led to increased cisplatin resistance. Induction of wild type p53 in STAT3-DN-transfected cells further diminished the chemoresistance and tumor growth through the upregulation of the MAPK- and PI3K/AKT-mediated ERS and autophagy. Introduction of STAT3-DN deprived the RASV12-induced ERS, autophagy, oncogenicity, and cisplatin resistance, whereas introduction of p53 in STAT3-DN/RASV12 expressing cells induced additional tumor retardation and cisplatin sensitivity. Thus, our data provide strong evidence that the crosstalk between STAT3 and p53/RAS signaling controls ovarian cancer cell metastasis and cisplatin resistance via the Slug/MAPK/PI3K/AKT-mediated regulation of EMT and autophagy.
Highlights
Ovarian carcinoma is the most lethal gynecological malignancy, which ranks the fifth leading cause of cancer death among women[1,2]
We found that the expression of pSTAT3 (Y705) was higher in HEY and SKOV3 cells than in A2780 and OVCA429 cells (Fig. 1a), and the expression levels of signal transducer and activator of transcription 3 (STAT3) and pSTAT3 S727 were higher in SKOV3 cells than in A2780, HEY and OVCA429 cells
These results demonstrate that the phosphorylation of STAT3 at Y705 but not S727 controls cell proliferation
Summary
Ovarian carcinoma is the most lethal gynecological malignancy, which ranks the fifth leading cause of cancer death among women[1,2]. When cells encounter stresses from extracellular stimuli, autophagy could be induced to form autophagosomes to initiate a self-eating cellular process through which harmful. Autophagy may contribute to either chemoresistance or chemosensitivity through different signaling contexts under specific conditions in different cancer types[6,7]. Recent literatures have endorsed the growing evidence that autophagy could be differentially regulated by signal transducer and activator of transcription 3 (STAT3): nuclear STAT3 may finely regulate autophagy via the transcriptional regulation of several autophagy-related genes; whereas cytoplasmic STAT3 can inhibit autophagy by sequestering EIF2AK2 and interacting with other molecules such as FOXO1 and FOXO3, and the mitochondrial STAT3 suppresses the oxidative stress-induced autophagy and reserves mitochondria from being degraded by mitophagy[8]. The signaling pathways involved in the STAT3-associated autophagy are quite intricate in terms of cancer cell chemoresistance
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