Galectins and galectin-mediated autophagy regulation: new insights into targeted cancer therapy

Abstract

Galectins are animal lectins with specific affinity for galactosides via the conserved carbohydrate recognition domains. Increasing studies recently have identified critical roles of galectin family members in tumor progression. Abnormal expression of galectins contributes to the proliferation, metastasis, epithelial-mesenchymal transformation (EMT), immunosuppression, radio-resistance and chemoresistance in various cancers, which has attracted cumulative clinical interest in galectin-based cancer treatment. Galectin family members have been reported to participate in autophagy regulation under physiological conditions and in non-tumoral diseases, and implication of galectins in multiple processes of carcinogenesis also involves regulation of autophagy, however, the relationship between galectins, autophagy and cancer remains largely unclear. In this review, we introduce the structure and function of galectins at the molecular level, summarize their engagements in autophagy and cancer progression, and also highlight the regulation of autophagy by galectins in cancer as well as the therapeutic potentials of galectin and autophagy-based strategies. Elaborating on the mechanism of galectin-regulated autophagy in cancers will accelerate the exploitation of galectins-autophagy targeted therapies in treatment for cancer.

Keywords: Autophagy; Cancer therapy; Clinical trials; Galectin.

Fig. 1

Gene and protein structures of galectins. A Prototype galectins that contain a CRD capable of forming monomers or non-covalent homodimers. B Tandem repeat galectins. Two different but homologous CRDs connected by a functional linker peptide, present in monomeric or oligomeric form. C Chimera galectins consist of an approximate 120-amino acid N-terminus attached to a CRD and form oligomers with increased binding affinity. Members of galectin families not discovered in humans are marked in purple. Representative gene structures are illustrated as indicated

Fig. 2

Schematic overview of the autophagy pathway and modulators. AMPK: adenosine monophosphate (AMP)-activated protein kinase; mTORC1: mammalian target of rapamycin complex 1; ULK: Unc-51-like kinase; ATG: autophagy-related gene; FIP200: focal adhesion kinase (FAK) family-interacting protein of 200 kDa; VPS34: vacuolar protein sorting 34; PI3K: phosphoinositide-3-kinase; LC3; PE: phosphatidylethanolamine

Fig. 3

Roles of galectins in autophagy. A Gal-8 promotes antibacterial autophagy by recognizing host glycans on ruptured vacuolar membranes and interacting with the autophagy adaptor protein NDP52. Autophagy receptor Tollip facilitates bacterial autophagy by recruiting Gal-7 in Response to bacterial Infection. Gal-3 accumulates at damaged phagosomes containing bacteria leading to a stronger anti-autophagic response. B Galectins recognize membrane damage by binding to lumenal glycans upon their exposure to the cytosol following endomembrane damage. During lysosomal damage, Gal-8 interacts with SLC38A9-Ragulator-mTOR complex and inhibits mTOR activity thereby inducing autophagy, whereas Gal-9 activates AMPK in response to lysosomal injury by promoting ubiquitination of TAK1. TRIM16 interacts with Gal-3 in response to damaged endomembrane

Fig. 4

Galectins are involved in autophagy regulation in tumors. A Shikonin induces ROS accumulation and dimerization of Gal-1 in human colorectal cancer cells by inhibiting the degradation of autophagolysosomes. B In hepatoma microenvironment, secreted Gal-1 binds to hepatoma cells and triggers autophagic flux via inhibiting AKT-mTOR activities. Gal-1-induced autophagy can target damaged mitochondria to reduce both mitochondrial membrane potential loss and cell death under cisplatin treatment. C Gal-3 acts as a negative regulator of autophagy in melanoma cells. Gal-3 inhibition increases autolysosome formation and resistance of melanoma cells to vemurafenib. D Gal-3 is upregulated under nutrient deprivation and hypoxia in pancreatic cancer which enhances the autophagic flux in tumor cells. E In KRAS^mut colorectal cancer (CRC), rLGALS9 acts as a lysosomal inhibitor and inhibits autophagosome-lysosome fusion, leading to autophagosome accumulation, excessive lysosomal swelling and cell death