title: GAIP interacting protein C-terminus regulates autophagy and exosome biogenesis of pancreatic cancer through metabolic pathways.
abstract: GAIP interacting protein C terminus (GIPC) is known to play an important role in a variety of physiological and disease states. In the present study, we have identified a novel role for GIPC as a master regulator of autophagy and the exocytotic pathways in cancer. We show that depletion of GIPC-induced autophagy in pancreatic cancer cells, as evident from the upregulation of the autophagy marker LC3II. We further report that GIPC regulates cellular trafficking pathways by modulating the secretion, biogenesis, and molecular composition of exosomes. We also identified the involvement of GIPC on metabolic stress pathways regulating autophagy and microvesicular shedding, and observed that GIPC status determines the loading of cellular cargo in the exosome. Furthermore, we have shown the overexpression of the drug resistance gene ABCG2 in exosomes from GIPC-depleted pancreatic cancer cells. We also demonstrated that depletion of GIPC from cancer cells sensitized them to gemcitabine treatment, an avenue that can be explored as a potential therapeutic strategy to overcome drug resistance in cancer.
authors.affiliation: Department Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Santanu
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Department Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Krishnendu
authors.initials: K
authors.lastname: Pal
authors.affiliation: Department Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sharma
authors.affiliation: Department Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Shamit K
authors.initials: SK
authors.lastname: Dutta
authors.affiliation: Department Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Julie S
authors.initials: JS
authors.lastname: Lau
authors.affiliation: Departments of Transplantation and Cancer Biology, Mayo Clinic, Jacksonville, Florida, United States of America.
authors.forename: Irene K
authors.initials: IK
authors.lastname: Yan
authors.affiliation: Department Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Enfeng
authors.initials: E
authors.lastname: Wang
authors.affiliation: Department Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Elkhanany
authors.affiliation: Department Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America; Department of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Alkharfy
authors.affiliation: Department Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Arunik
authors.initials: A
authors.lastname: Sanyal
authors.affiliation: Departments of Transplantation and Cancer Biology, Mayo Clinic, Jacksonville, Florida, United States of America.
authors.forename: Tushar C
authors.initials: TC
authors.lastname: Patel
authors.affiliation: Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Suresh T
authors.initials: ST
authors.lastname: Chari
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, and Norris Cotton Cancer Center, Lebanon, New Hampshire, United States of America.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Spaller
authors.affiliation: Department Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukhopadhyay
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D001692:Biological Transport; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D055354:Exosomes / Q000378:metabolism*; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D013312:Stress, Physiological; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D048868:Adaptor Proteins, Signal Transducing; D000964:Antimetabolites, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C492009:GIPC1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D003841:Deoxycytidine; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; D005947:Glucose; D000093542:Gemcitabine