Resveratrol Contrasts IL-6 Pro-Growth Effects and Promotes Autophagy-Mediated Cancer Cell Dormancy in 3D Ovarian Cancer: Role of miR-1305 and of Its Target ARH-I

Abstract

Tumor dormancy is the extended period during which patients are asymptomatic before recurrence, and it represents a difficult phenomenon to target pharmacologically. The relapse of tumors, for instance arising from the interruption of dormant metastases, is frequently observed in ovarian cancer patients and determines poor survival. Inflammatory cytokines present in the tumor microenvironment likely contribute to such events. Cancer cell dormancy and autophagy are interconnected at the molecular level through ARH-I (DIRAS3) and BECLIN-1, two tumor suppressors often dysregulated in ovarian cancers. IL-6 disrupts autophagy in ovarian cancer cells via miRNAs downregulation of ARH-I, an effect contrasted by the nutraceutical protein restriction mimetic resveratrol (RV). By using three ovarian cancer cell lines with different genetic background in 2D and 3D models, the latter mimicking the growth of peritoneal metastases, we show that RV keeps the cancer cells in a dormant-like quiescent state contrasting the IL-6 growth-promoting activity. Mechanistically, this effect is mediated by BECLIN-1-dependent autophagy and relies on the availability of ARH-I. We also show that ARH-I (DIRAS3) is a bona fide target of miR-1305, a novel oncomiRNA upregulated by IL-6 and downregulated by RV. Clinically relevant, bioinformatic analysis of a transcriptomic database showed that the high expression of DIRAS3 and MAP1LC3B mRNAs together with that of CDKN1A, directing a cellular dormant phenotype, predicts better overall survival in ovarian cancer patients, and this correlates with MIR1305 downregulation. The possibility of maintaining a permanent cell dormancy in ovarian cancer by the chronic administration of RV should be considered as a therapeutic option to prevent the “awakening” of cancer cells in response to a permissive microenvironment, thus limiting the risk of tumor relapse and metastasis.

Glycolysis Inhibition of Autophagy Drives Malignancy in Ovarian Cancer: Exacerbation by IL-6 and Attenuation by Resveratrol

“…The high glucose uptake induced by IL-6 associated with increased levels of ROS (red signal), was more evident in OVCAR3 cells. In a separate study, we showed that under this condition cell viability is however not affected [ 17 ]. MB contrasted the production of anion superoxide induced by IL-6, confirming that these ROS arose from overwhelming the respiratory chain caused by increased glycolytic flux ( Figure 3 A).…”

“…In the last years, the anti-cancer properties of natural compounds, along with their low toxic side effects, have attracted the interest of researchers [ 39 ]. Our group extensively reported the beneficial effects of the nutraceutical resveratrol (RV) that acts as a potent autophagy inducer, caloric restriction mimetic, and is capable to modulate the epigenome of the cancer cells, the secretion of cytokines and mitogenic factors, and to limit angiogenesis, immune suppression, and the activation of cancer-associated fibroblasts [ 16 , 17 , 18 , 19 , 20 , 27 , 40 ]. In the present work, we found that RV counteracts ovarian cancer cell migration by mimicking the phenotypic changes observed in glucose deprivation.…”

“…IL-6 accumulates in the serum and ascitic liquid of ovarian cancer patients [ 14 ], correlating with metastasis and poor clinical outcome [ 15 ]. We demonstrated that IL-6 positively impinges on ovarian cancer cell proliferation and motility via epigenetic down-regulation of autophagy [ 16 , 17 ]. We also showed that the nutraceutical resveratrol (RV) contrasts the oncogenic activities of IL-6 in the tumor microenvironment, acting as a potent inducer of autophagy and modulator of the transcriptome and epigenome [ 16 , 17 , 18 , 19 , 20 ].…”

Resveratrol and Its Analogue 4,4′-Dihydroxy-trans-stilbene Inhibit Lewis Lung Carcinoma Growth In Vivo through Apoptosis, Autophagy and Modulation of the Tumour Microenvironment in a Murine Model

“…The induction of autophagy by RSV has been reported in many in vitro studies, and here we have confirmed such effect in a syngeneic mouse model of lung cancer. Remarkably, we have previously demonstrated that RSV-induced autophagy can oppose ovarian cancer cell migration and proliferation while supporting a dormant phenotype [ 58 , 59 , 60 ].…”

Signaling by LncRNAs: Structure, Cellular Homeostasis, and Disease Pathology

“…In normal cellular homeostasis of cardiomyocytes, H19 downregulates DIRAS3 (distinct subgroup of the Ras family member 3) expression through the recruitment of EZH2 to induce H3K27me3 methylation on the DIRAS3 promoter [ 188 ]. DIRAS3 inhibits cell proliferation and promotes autophagy-mediated cell dormancy [ 224 ]. Downregulation of H19 observed in DCM leads to the depression of DIRAS3 and the resultant inhibition of Akt-signaling pathway and autophagy of cardiomyocytes, promoting DCM [ 188 ].…”