ESPELT Maria Victoria
22. Galectin-1 confers resistance to doxorubicin in hepatocellular carcinoma cells through modulation of P-glycoprotein expression
CARABIAS, P; ESPELT M.V; BACIGALUPO ML; ROJAS P; SARRIAS L; RUBIN A; SAFFIOTI, N; ELOLA MT; ROSSI JP; CARLOTA WOLFENSTEIN-TODEL; GABRIEL A. RABINOVICH; TRONCOSO MF
Cell Death and Disease
Nature Publishing Group
Galectin-1 (GAL1), a β-galactoside-binding protein abundantly expressed in the tumor microenvironment, has emerged as a keymechanism of chemoresistance developed by different tumors. Although increased expression of GAL1 is a hallmark ofhepatocellular carcinoma (HCC) progression, aggressiveness and metastasis, limited information is available on the role of thisendogenous lectin in HCC resistance to chemotherapy. Moreover, the precise mechanisms underlying this effect are uncertain. HCChas evolved different mechanisms of resistance to chemotherapy including those involving the P-glycoprotein (P-gp), an ATPdependent drug efflux pump, which controls intracellular drug concentration. Here, we investigated the molecular mechanismunderlying GAL1-mediated chemoresistance in HCC cells, particularly the involvement of P-gp in this effect. Our results show thatGAL1 protected HepG2 cells from doxorubicin (DOX)- and sorafenib-induced cell death in vitro. Accordingly, GAL1-overexpressingHepG2 cells generated DOX-resistant tumors in vivo. High expression of GAL1 in HepG2 cells reduced intracellular accumulation ofDOX likely by increasing P-gp protein expression rather than altering its membrane localization. GAL1-mediated increase of P-gpexpression involved activation of the phosphatidylinositol-3 kinase (PI3K) signaling pathway. Moreover, ?loss-of-function?experiments revealed that P-gp mediates GAL1-driven resistance to DOX, but not to sorafenib, in HepG2 cells. Conversely, in PLC/PRF/5 cells, P-gp protein expression was undetectable and GAL1 did not control resistance to DOX or sorafenib, supporting thecritical role of P-gp in mediating GAL1 effects. Collectively, our findings suggest that GAL1 confers chemoresistance in HCC throughmechanisms involving modulation of P-gp, thus emphasizing the role of this lectin as a potential therapeutic target in HCC.