Rescuing SLAMF3 Expression Restores Sorafenib Response in Hepatocellular Carcinoma Cells through the Induction of Mesenchymal-to-Epithelial Transition

Abstract

Background: Acquired resistance to sorafenib in hepatocellular carcinoma (HCC) patients results in poor prognosis. Epithelial-to-mesenchymal transition (EMT) is the major mechanism implicated in the resistance to sorafenib. We have reported the tumor suppressor role of SLAMF3 (signaling lymphocytic activation molecules family 3) in HCC progression and highlighted its implication in controlling the MRP-1 transporter activity. These data suggest the implication of SLAMF3 in sorafenib resistance mechanisms. Methods: We evaluated the resistance to sorafenib in Huh-7 cells treated with progressive doses (Res cells). We investigated the link between acquired resistance to sorafenib and SLAMF3 expression by flow cytometry and Western blot methods. Furthermore, we analyzed the EMT and the stem cell potential of cells resistant to sorafenib. Results: Sorafenib resistance was confirmed in Res cells by analyzing the cell viability in the presence of sorafenib. The mesenchymal transition, in Res cells, was confirmed by high migratory index and the expression of EMT antigens. Interestingly, we found that loss of SLAMF3 expression corresponded to sorafenib-resistant phenotypes. The overexpression of SLAMF3 reversed EMT, decreased metastatic potential and inhibited mTOR/ERK1/2 in Res cells. Conclusions: We propose that rescuing SLAMF3 expression in resistant cells could represent a potential therapeutic strategy to enhance sorafenib efficacy in HCC patients.

Sorafenib Chemosensitization by Caryophyllane Sesquiterpenes in Liver, Biliary, and Pancreatic Cancer Cells: The Role of STAT3/ABC Transporter Axis

“…Several studies have demonstrated that ABC transporters play a central role in sorafenib resistance [39]. Indeed, different pumps, including MDR1, MRP1, MRP2, MRP3, and BCRP, have been reported to export the anticancer drug from cells, and thus are associated with sorafenib resistance [49][50][51]. In this landscape, we decide to investigate the effect of caryophyllane sesquiterpenes towards MDR1, MRP1, and MRP2 pumps based on the results obtained in our previous work, which highlighted a lower effect of these compounds on MRP3 transporter [20].…”

Emerging phagocytosis checkpoints in cancer immunotherapy

“…SFRs can work in combination with the CD47 pathway but function independently of CD47 to mitigate macrophage phagocytosis. 163 SLAMF3 is also expressed in cancer cells, 164 but its function in phagocytosis in cancer immunotherapy remains unclear.…”

The advancements in targets for ferroptosis in liver diseases

“…Therefore, researchers investigated the induction of ferroptosis in HCC cells. Sorafenib is currently used as the first-line drug for the treatment of advanced HCC, and studies have shown that it could induce ferroptosis of HCC cells and thereby inhibit their proliferation ( 18 ). And the efficacy of sorafenib was affected by intracellular genetic status; for example, Rb-negative hepatoma cells were more sensitive to sorafenib-induced ferroptosis ( 19 ).…”