title: The epithelial polarity regulator LGALS9/galectin-9 induces fatal frustrated autophagy in KRAS mutant colon carcinoma that depends on elevated basal autophagic flux.
abstract: Oncogenic mutation of KRAS (Kirsten rat sarcoma viral oncogene homolog) in colorectal cancer (CRC) confers resistance to both chemotherapy and EGFR (epidermal growth factor receptor)-targeted therapy. We uncovered that KRAS mutant (KRAS(mut)) CRC is uniquely sensitive to treatment with recombinant LGALS9/Galectin-9 (rLGALS9), a recently established regulator of epithelial polarity. Upon treatment of CRC cells, rLGALS9 rapidly internalizes via early- and late-endosomes and accumulates in the lysosomal compartment. Treatment with rLGALS9 is accompanied by induction of frustrated autophagy in KRAS(mut) CRC, but not in CRC with BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations (BRAF(mut)). In KRAS(mut) CRC, rLGALS9 acts as a lysosomal inhibitor that inhibits autophagosome-lysosome fusion, leading to autophagosome accumulation, excessive lysosomal swelling and cell death. This antitumor activity of rLGALS9 directly correlates with elevated basal autophagic flux in KRAS(mut) cancer cells. Thus, rLGALS9 has potent antitumor activity toward refractory KRAS(mut) CRC cells that may be exploitable for therapeutic use.
authors.affiliation: a University of Groningen; University Medical Center Groningen; Department of Surgery; Translational Surgical Oncology ; Groningen , The Netherlands.
authors.forename: Valerie R
authors.initials: VR
authors.lastname: Wiersma
authors.forename: Marco
authors.initials: M
authors.lastname: de Bruyn
authors.forename: Yunwei
authors.initials: Y
authors.lastname: Wei
authors.forename: Robert J
authors.initials: RJ
authors.lastname: van Ginkel
authors.forename: Mitsuomi
authors.initials: M
authors.lastname: Hirashima
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niki
authors.forename: Nozomu
authors.initials: N
authors.lastname: Nishi
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.forename: Simon D
authors.initials: SD
authors.lastname: Pouwels
authors.forename: Douwe F
authors.initials: DF
authors.lastname: Samplonius
authors.forename: Hans W
authors.initials: HW
authors.lastname: Nijman
authors.forename: Paul
authors.initials: P
authors.lastname: Eggleton
authors.forename: Wijnand
authors.initials: W
authors.lastname: Helfrich
authors.forename: Edwin
authors.initials: E
authors.lastname: Bremer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D001343:Autophagy; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002470:Cell Survival; D002966:Clathrin / Q000737:chemistry; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism*; D037161:Galectins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation; D009368:Neoplasm Transplantation; D010588:Phagosomes / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D002966:Clathrin; D037161:Galectins; C117307:KRAS protein, human; C105032:LGALS9 protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS mutation; autophagy; colon cancer; galectin-9; lysosomes