GAIP Interacting Protein C-Terminus Regulates Autophagy and Exosome Biogenesis of Pancreatic Cancer through Metabolic Pathways

Bhattacharya, Santanu; Pal, Krishnendu; Sharma, Anil Kumar; Dutta, Shamit K.; Lau, Julie S.; Yan, Irene K.; Wang, Enfeng; Elkhanany, Ahmed; Alkharfy, Khalid M.; Sanyal, Abhik Kumar; Patel, Tushar; Chari, Suresh T.; Spaller, Mark R.; Mukhopadhyay, Debabrata

doi:10.1371/journal.pone.0114409

Cited by 62 publications

(55 citation statements)

References 54 publications

(63 reference statements)

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“…50,51 Few of the tested markers showed decreasing transcript levels including ALIX, which was one of the most widely examined exosome markers in cancer development. 29,30,52,53 Our gene expression data correlated well with those gained from independent databases, [36][37][38][39] showing similarly reduced ALIX mRNA levels during adenoma-carcinoma sequence, which was also validated at the in situ protein level. Similar alterations between whole biopsy mRNA and protein level in epithelial compartment suggest that the majority of ALIX originated from these components.…”

Section: Discussionsupporting

confidence: 78%

Exosomes in colorectal carcinoma formation: ALIX under the magnifying glass

et al. 2016

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Exosomes are small membrane vesicles that have important roles in transporting a great variety of bioactive molecules between epithelial compartment and their microenvironment during tumor formation including colorectal adenoma-carcinoma sequence. We tested the mRNA expression of the top 25 exosome-related markers based on ExoCharta database in healthy (n = 49), adenoma (n = 49) and colorectal carcinoma (n = 49) patients using Affymetrix HGU133 Plus2.0 microarrays. Most related genes showed significantly elevated expression including PGK1, PKM, ANXA5, ENO1, HSP90AB1 and MSN during adenoma-carcinoma sequence. Surprisingly, the expression of ALIX (ALG 2-interacting protein X), involved in multivesicular body (MVB) and exosome formation, was significantly reduced in normal vs adenoma (P = 5.02 × 10 − 13 ) and in normal vs colorectal carcinoma comparisons (P = 1.51 × 10 − 10 ). ALIX also showed significant reduction (Po 0.05) at the in situ protein level in the epithelial compartment of adenoma (n = 35) and colorectal carcinoma (n = 37) patients compared with 27 healthy individuals. Furthermore, significantly reduced ALIX protein levels were accompanied by their gradual transition from diffuse cytoplasmic expression to granular signals, which fell into the 0.6-2 μm diameter size range of MVBs. These ALIX-positive particles were seen in the tumor nests, including tumorstroma border, which suggest their exosome function. MVB-like structures were also detected in tumor microenvironment including α-smooth muscle actin-positive stromal cells, budding off cancer cells in the tumor front as well as in cancer cells entrapped within lymphoid vessels. In conclusion, we determined the top aberrantly expressed exosome-associated markers and revealed the transition of diffuse ALIX protein signals into a MVB-like pattern during adenoma-carcinoma sequence. These tumor-associated particles seen both in the carcinoma and the surrounding microenvironment can potentially mediate epithelial-stromal interactions involved in the regulation of tumor growth, metastatic invasion and therapy response.

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Section: Discussionsupporting

confidence: 78%

Exosomes in colorectal carcinoma formation: ALIX under the magnifying glass

et al. 2016

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“…It is also possible that, in the scenario of HSC activation and increased HSC autophagy, the upregulation of synectin may protect PDGFR-α from degradation. Increasing evidence suggests that RTKs and other signaling proteins can also be regulated and degraded through selective autophagy, including EGFR (37), FLT3 (38), GLUT1 (39), and Src (40). Synectin shares the same myosin VI binding site as target of Myb1 membrane trafficking protein 1 (TOM1), a known autophagy mediator, thus supporting the premise that synectin can regulate the autophagic fate of specific proteins (41).…”

Section: Discussionmentioning

confidence: 90%

Synectin promotes fibrogenesis by regulating PDGFR isoforms through distinct mechanisms

Drinane¹,

Yaqoob²,

Yu³

et al. 2017

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“…Several studies have described the link between autophagy and exosome biogenesis in disease. Bhattacharya described how both mechanisms work together in pancreatic tumour cells . Wang described how autophagy and RPE exosomes work together in the formation of drusen in AMD .…”

Section: Discussionmentioning

confidence: 99%

Role of retinal pigment epithelium‐derived exosomes and autophagy in new blood vessel formation

Atienzar‐Aroca

Serrano‐Heras

Valls

et al. 2018

J Cellular Molecular Medi

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Autophagy and exosome secretion play important roles in a variety of physiological and disease states, including the development of age‐related macular degeneration. Previous studies have demonstrated that these cellular mechanisms share common pathways of activation. Low oxidative damage in ARPE‐19 cells, alters both autophagy and exosome biogenesis. Moreover, oxidative stress modifies the protein and genetic cargo of exosomes, possibly affecting the fate of surrounding cells. In order to understand the connection between these two mechanisms and their impact on angiogenesis, stressed ARPE‐19 cells were treated with a siRNA‐targeting Atg7, a key protein for the formation of autophagosomes. Subsequently, we observed the formation of multivesicular bodies and the release of exosomes. Released exosomes contained VEGFR2 as part of their cargo. This receptor for VEGF—which is critical for the development of new blood vessels—was higher in exosome populations released from stressed ARPE‐19. While stressed exosomes enhanced tube formation, exosomes became ineffective after silencing VEGFR2 in ARPE‐19 cells and were, consequently, unable to influence angiogenesis. Moreover, vessel sprouting in the presence of stressed exosomes seems to follow a VEGF‐independent pathway. We propose that abnormal vessel growth correlates with VEGFR2‐expressing exosomes release from stressed ARPE‐19 cells, and is directly linked to autophagy.

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GAIP Interacting Protein C-Terminus Regulates Autophagy and Exosome Biogenesis of Pancreatic Cancer through Metabolic Pathways

Cited by 62 publications

References 54 publications

Exosomes in colorectal carcinoma formation: ALIX under the magnifying glass

Exosomes in colorectal carcinoma formation: ALIX under the magnifying glass

Synectin promotes fibrogenesis by regulating PDGFR isoforms through distinct mechanisms

Role of retinal pigment epithelium‐derived exosomes and autophagy in new blood vessel formation

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