Visfatin induces ovarian cancer resistance to anoikis by regulating mitochondrial activity

Abstract

Purpose Ovarian cancer is characterized by recurrent peritoneal and distant metastasis. To survive in a non-adherent state, floating ovarian cancer spheroids develop mechanisms to resist anoikis. Moreover, ascitic fluid from ovarian cancer patients contains high levels of visfatin with anti-apoptotic properties. However, the mechanism by which visfatin induces anoikis resistance in ovarian cancer spheroids remains unknown. Here, we aimed to assess wheather visfatin which possess anti-apoptotic properties can induce resistance of anoikis in ovarian cancer spheroids. Methods Visfatin synthesis were examined using a commercial human visfatin ELISA Kit. Spheroid were exposed to visfatin and cell viability and caspase 3/7 activity were measured using CellTiter-Glo 3D cell viability assay and Caspase-Glo® 3/7 Assay System. mRNA and protein expression were analyzed by Real-time PCR and Western Blot analysis, respectively. Analysis of mitochondrial activity was estimated by JC-1 staining. Results First, our results suggested higher expression and secretion of visfatin by epithelial than by granulosa ovarian cells, and in non-cancer tissues versus cancer tissues. Interestingly, visfatin increased the proliferation/apoptosis ratio in ovarian cancer spheroids. Specifically, both the intrinsic and extrinsic pathways of anoikis were regulated by visfatin. Moreover, the effect of the visfatin inhibitor (FK866) was opposite to that of visfatin. Furthermore, both NAMPT and FK866 affected mitochondrial activity in ovarian cancer cells. Conclusion In conclusion, visfatin acts as an anti-apoptotic factor by regulating mitochondrial activity, leading to anoikis resistance in ovarian cancer spheroids. The finding suggest visfatin as a potential novel therapeutic target for the treatment of ovarian carcinoma with peritoneal dissemination.

Identification and Validation of a Novel Anoikis-Related Gene Signature for Predicting Survival in Patients With Serous Ovarian Cancer

“…Recent research found the regulation of mitochondrial activity can lead to ovarian cancer spheroids becoming resistant to anoikis. This finding suggests that targeting anoikis resistance may be a promising approach for treating peritoneal metastasis in SOC [ 22 ]. However, there is a lack of research examining the potential predictive significance of anoikis in SOC patients by using bioinformatics techniques.…”

Evaluation of the Potential Diagnostic Utility of the Determination of Selected Immunological and Molecular Parameters in Patients with Ovarian Cancer

“…It is one of the components in the link between adipose tissue and the inflammatory response, but the mechanism has not been fully explored [92]. Research by Gogola-Mruk J. et al [100] demonstrates that visfatin acts as an anti-apoptotic factor by regulating mitochondrial activity, leading to resistance to anoikis in ovarian cancer spheroids. These findings suggest that visfatin is a potential new therapeutic target for the treatment of ovarian cancer with peritoneal dissemination [100].…”

“…Research by Gogola-Mruk J. et al [100] demonstrates that visfatin acts as an anti-apoptotic factor by regulating mitochondrial activity, leading to resistance to anoikis in ovarian cancer spheroids. These findings suggest that visfatin is a potential new therapeutic target for the treatment of ovarian cancer with peritoneal dissemination [100]. Results from Nacarelli T. et al [101] suggest that NAMPT inhibitors (such as FK866) may be repurposed to suppress therapy-induced senescence-associated CSCs for improving platinum-based standard of care, a major obstacle in the clinical management of EOC [101].…”

“…Table 3. Role of selected adipocytokines in ovarian cancer [80,82,84,86,89,91,96,97,[99][100][101]106,108,109,[112][113][114].…”

“…Leptin high co-expression of LEP and LEPR correlating with poor survival of ovarian cancer patients; leptin/LEPR signalling via JAK2/STAT3 has the potential to significantly impact pathogenesis in a subset of ovarian cancer patients [84] stimulation of proliferation of ovarian cancer cell lines in vitro [80] association of overexpression of leptin and its receptor in tissue with aggressive nature of the disease [86] stimulation of proliferation and inhibition of apoptosis through activation of PI3K/AKT signalling pathway [82] Resistin positive correlation between expression levels or the degree of EOC differentiation and lymph node metastasis [89,91] association of serum levels with chronic inflammation, leading to the induction of ovarian carcinogenesis [80] Adiponectin concentration lower in ovarian cancer patients than in controls; no association with stage of disease progression [96] no association of concentration with stage of disease and response to treatment [97] concentration higher in ovarian cancer patients than in controls; relationship of expression to FIGO stage [99] Visfatin anti-apoptotic factor leading to anoikis resistance in ovarian cancer spheroids [100] NAMPT inhibition suppresses senescence-associated CSCs induced by platinum-based chemotherapy in EOC [101] Chemerin promotion of proliferation and migration of ovarian cancer cells by upregulating expression of PD-L1 [104] activation of IFNα response by chemerin; increased production of IFNα protein in ovarian cancer cells and reduction in cancer cell numbers in vitro [106] Apelin BPA and its derivatives induce ovarian cancer cell progression by up-regulating apelin, which acts as a mitogenic factor in these cells [108] increased APJ expression significantly correlates with decreased median overall survival [109] Omentin activation of the PI3k/Akt pathway [112] no relationship between ITNL1 levels in patients with ovarian cancer and healthy control [113] relationship between ITLN1 in patients with high-grade ovarian cancer, healthy women and women with benign gynaecologic disease [114] 4.3. Cancer Stem Cells (CSCs)…”