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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism
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Adaptor Proteins, Signal Transducing / physiology*
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Antimetabolites, Antineoplastic / pharmacology
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Apoptosis Regulatory Proteins / metabolism
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Autophagy*
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Autophagy-Related Protein 7
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Beclin-1
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Biological Transport
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Cell Line, Tumor
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Deoxycytidine / analogs & derivatives
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Deoxycytidine / pharmacology
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Drug Resistance, Neoplasm
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Exosomes / metabolism*
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Gemcitabine
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Gene Expression
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Glucose / metabolism
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Humans
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Membrane Proteins / metabolism
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Metabolic Networks and Pathways
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Pancreatic Neoplasms / metabolism*
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Pancreatic Neoplasms / pathology
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Stress, Physiological
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Ubiquitin-Activating Enzymes / metabolism
Substances
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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Adaptor Proteins, Signal Transducing
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Antimetabolites, Antineoplastic
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Apoptosis Regulatory Proteins
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BECN1 protein, human
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Beclin-1
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GIPC1 protein, human
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Membrane Proteins
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Neoplasm Proteins
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Deoxycytidine
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ATG7 protein, human
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Autophagy-Related Protein 7
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Ubiquitin-Activating Enzymes
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Glucose
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Gemcitabine