Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers in Taiwan. Although chemotherapy is the primary treatment for HCC patients, drug resistance often leads to clinical failure. Galectin-1 is a beta-galactoside binding lectin which is up-regulated in HCC patients and promotes tumor growth by mediating cancer cell adhesion, migration and proliferation, but its role in chemoresistance of HCC is poorly understood. In this study we found that galectin-1 is able to lead to chemoresistance against cisplatin treatment, and subsequent inhibition has reversed the effect of cell death in HCC cells. Moreover, galectin-1 was found to induce autophagic flux in HCC cells. Inhibition of autophagy by inhibitors or knockdown of Atg5 cancels galectin-1-induced cisplatin resistance in HCC cells. Increase of mitophagy triggered by galectin-1 was found to reduce the mitochondrial potential loss and apoptosis induced by cisplatin treatment. Finally, using an in situ hepatoma mouse model, we clearly demonstrated that inhibition of galectin-1 by thiodigalactoside could significantly augment the anti-HCC effect of cisplatin. Taken together, our findings offer a new insight into the chemoresistance galectin-1 causes against cisplatin treatment, and points to a potential approach to improve the efficacy of cisplatin in the treatment of HCC patients.
Highlights
Diagnosed worldwide, one million people are suffering from liver cancer [1], which ranks the fifth most common cancer, and comes third in cancer-related deaths
In our study we found that exogenous galectin1 is able to induce chemoresistance to cisplatin in hepatoma cells
This chemoresistance induced by soluble galectin-1 is facilitated through the induction of Bcl-2/adenovirus E1B kDainteracting protein 3 (BNIP3)-related autophagy and by downregulating the mTORC signaling
Summary
One million people are suffering from liver cancer [1], which ranks the fifth most common cancer, and comes third in cancer-related deaths. A preponderance of cases occurs in Asia and Africa, an upsurge of the mortality rate has been found in North America and Europe [2, 3]. Risk factors such as hepatitis infection, alcohol related cirrhosis, and nonalcoholic fatty liver diseases are considered to influence the increasing the number of HCC cases. Galectin-1 on Cisplatin Resistance in both developed countries and low risk areas[4, 5]. Treatment with anti-cancer drugs to destroy cancer cells (chemotherapy) can help patients to control cancer growth, liver cancer patients always develop drug resistance to chemotherapy. The mechanism of developing chemoresistance is not fully understood, recent evidence has shown that tumor microenvironmental stress-induced autophagy may contribute in part [6]
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