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.
Highlights
Macroautophagy, commonly termed as autophagy, is an essential catabolic process that cells implement in diverse biological and physiological activities [1, 2]
Utilizing the GAIP interacting protein C terminus (GIPC)-depleted AsPC-1 and PANC-1 pancreatic cell lines, we investigated whether GIPC modulated autophagy by assessing the autophagyrelated microtubule-associated protein light chain 3 (LC3) conversions (LC3-I to light chain 3-II (LC3-II)) via Western blot analysis
It is well known that the conversion of the light chain 3-I (LC3-I), upon conjugation to phosphatidylethanolamine (PE), forms the conjugate light chain 3-II (LC3-II) which is recruited to the membranes of autophagosomes [13, 20]
Summary
Macroautophagy, commonly termed as autophagy, is an essential catabolic process that cells implement in diverse biological and physiological activities [1, 2]. It was believed that the autophagosome, a double-membraned vesicle, engulfs organelles randomly [1, 2, 5]; recent studies have shown that the selection of organelles is directed by cargo specific factors [6]. Autophagy plays an important role in many disease processes, including cancer [7]. Because mutations of autophagy-related genes have been reported in human cancers [10, 11], studies have focused on genetic and chemical inhibition of autophagy as a therapeutic strategy [12]
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