The role of galectin-3 in cancer drug resistance

Abstract

The galectins comprise a family of 14 members of beta-galactoside-binding proteins, characterized by their affinity for beta-galactosides and by a conserved sequence in the carbohydrate recognition domain that bind to the carbohydrate portion of cell surface glycoproteins or glycolipids. Galectin-3, a 31kDa gene product, is a multifunctional oncogenic protein which regulates cell growth, cell adhesion, cell proliferation, angiogenesis, and apoptosis. Recent studies have revealed that galectin-3 demonstrates anti-apoptotic effects which contribute to cell survival in several types of cancer cells. Intracellular galectin-3 in particular, which contains the NWGR anti-death motif of the Bcl-2 family, inhibits cell apoptosis induced by chemotherapeutic agent such as cisplatin and etoposide in some types of cancer cells. We have also reported that nuclear export of phosphorylated galectin-3 regulates its anti-apoptotic activity in response to chemotherapeutic drugs. Here, we will describe the role of galectin-3 as an anti-apoptotic factor in response to chemotherapeutic drugs and will discuss recent data on its molecular mechanism that contribute to drug resistance. We suggest that targeting galectin-3 could improve the efficacy of anticancer drug chemotherapy in several types of cancer.

Fig. 1

Structure and functional domain of galectin-3. Galectin-3 consists of three structural domains: (a) a NH₂-terminal domain of 12 amino acid that contains a serine phosphorylation site; (b) a repeated collagen-like sequence rich in glycine, proline, and tyrosine; and (c) a COOH-terminal carbohydrate recognition domain (CRD) consisting 140 amino acid residues. The C-terminal domain includes the NWGR motif which is highly conserved in the BH1 domain of the Bcl-2 gene family including Bcl-2, Bcl-xL, and Bax.

Fig. 2

Model for the regulation of apoptosis signaling pathways induced by anticancer drugs in galectin-3 expressing cells. Anticancer drugs can induce DNA damage, which causes phosphorylated galectin-3 to translocate from the nucleus to cytoplasm and regulates phosphorylation of Bad, Akt, and ERK resulting in stabilization of mitochondrial membrane integrity. The stabilization of the mitochondrial membrane prevents cytochrome c release and subsequent caspase activation, resulting in suppression of apoptosis and caused anticancer drug resistance.