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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.

SUBMITTER: Bhattacharya S

PROVIDER: S-EPMC4255029 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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GAIP interacting protein C-terminus regulates autophagy and exosome biogenesis of pancreatic cancer through metabolic pathways.

Bhattacharya Santanu S Pal Krishnendu K Sharma Anil K AK Sharma Anil K AK Dutta Shamit K SK Lau Julie S JS Yan Irene K IK Wang Enfeng E Elkhanany Ahmed A Alkharfy Khalid M KM Sanyal Arunik A Patel Tushar C TC Chari Suresh T ST Spaller Mark R MR Mukhopadhyay Debabrata D

PloS one 20141203 12

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 secretio ...[more]

PMID: 25469510

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Project description:Nutritional symbionts are restricted to specialized host cells called bacteriocytes in various insect orders. These symbionts can provide essential nutrients to the host. However, the cellular mechanisms underlying the regulation of these insect-symbiont metabolic associations remain largely unclear. The whitefly Bemisia tabaci MEAM1 hosts "Candidatus Portiera aleyrodidarum" (here, "Ca. Portiera") and "Candidatus Hamiltonella defensa" (here, "Ca. Hamiltonella") bacteria in the same bacteriocyte. In this study, the induction of autophagy by chemical treatment and gene silencing decreased symbiont titers and essential amino acid (EAA) and B vitamin contents. In contrast, the repression of autophagy in bacteriocytes via Atg8 silencing increased symbiont titers, and amino acid and B vitamin contents. Furthermore, dietary supplementation with non-EAAs or B vitamins alleviated autophagy in whitefly bacteriocytes, elevated TOR (target of rapamycin) expression, and increased symbiont titers. TOR silencing restored symbiont titers in whiteflies after dietary supplementation with B vitamins. These data suggest that "Ca. Portiera" and "Ca. Hamiltonella" evade autophagy of the whitefly bacteriocytes by activating the TOR pathway via providing essential nutrients. Taken together, we demonstrate that autophagy plays a critical role in regulating the metabolic interactions between the whitefly and two intracellular symbionts. Therefore, this study reveals that autophagy is an important cellular basis for bacteriocyte evolution and symbiosis persistence in whiteflies. The whitefly symbiosis unravels the interactions between cellular and metabolic functions of bacteriocytes. IMPORTANCE Nutritional symbionts, which are restricted to specialized host cells called bacteriocytes, can provide essential nutrients for many hosts. However, the cellular mechanisms of regulation of animal-symbiont metabolic associations have been largely unexplored. Here, using the whitefly-"Ca. Portiera"/"Ca. Hamiltonella" endosymbiosis, we demonstrate autophagy regulates the symbiont titers and thereby alters the essential amino acid and B vitamin contents. For persistence in the whitefly bacteriocytes, "Ca. Portiera" and "Ca. Hamiltonella" alleviate autophagy by activating the TOR (target of rapamycin) pathway through providing essential nutrients. Therefore, we demonstrate that autophagy plays a critical role in regulating the metabolic interactions between the whitefly and two intracellular symbionts. This study also provides insight into the cellular basis of bacteriocyte evolution and symbiosis persistence in the whitefly. The mechanisms underlying the role of autophagy in whitefly symbiosis could be widespread in many insect nutritional symbioses. These findings provide a new avenue for whitefly control via regulating autophagy in the future.

Project description:AimsIt has been reported that the G-alpha interacting protein (GAIP) interacting protein, C terminus 1 (GIPC1/GIPC) engages in vesicular trafficking, receptor transport and expression, and endocytosis. However, its role in epilepsy is unclear. Therefore, in this study, we aimed to explore the role of GIPC1 in epilepsy and its possible underlying mechanism.MethodsThe expression patterns of GIPC1 in patients with temporal lobe epilepsy (TLE) and in mice with kainic acid (KA)-induced epilepsy were detected. Behavioral video monitoring and hippocampal local field potential (LFP) recordings were carried out to determine the role of GIPC1 in epileptogenesis after overexpression of GIPC1. Coimmunoprecipitation (Co-IP) assay and high-resolution immunofluorescence staining were conducted to investigate the relationship between GIPC1 and metabotropic glutamate receptor 7 (mGluR7). In addition, the expression of mGluR7 after overexpression of GIPC1 was measured, and behavioral video monitoring and LFP recordings after antagonism of mGluR7 were performed to explore the possible mechanism mediated by GIPC1.ResultsGIPC1 was downregulated in the brain tissues of patients with TLE and mice with KA-induced epilepsy. After overexpression of GIPC1, prolonged latency period, decreased epileptic seizures and reduced seizure severity in behavioral analyses, and fewer and shorter abnormal brain discharges in LFP recordings of KA-induced epileptic mice were observed. The result of the Co-IP assay showed the interaction between GIPC1 and mGluR7, and the high-resolution immunofluorescence staining also showed the colocalization of these two proteins. Additionally, along with GIPC1 overexpression, the total and cell membrane expression levels of mGluR7 were also increased. And after antagonism of mGluR7, increased epileptic seizures and aggravated seizure severity in behavioral analyses and more and longer abnormal brain discharges in LFP recordings were observed.ConclusionGIPC1 regulates epileptogenesis by interacting with mGluR7 and increasing its expression.

Dataset Information

GAIP interacting protein C-terminus regulates autophagy and exosome biogenesis of pancreatic cancer through metabolic pathways.

Publications

GAIP interacting protein C-terminus regulates autophagy and exosome biogenesis of pancreatic cancer through metabolic pathways.

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