Universität zu Köln

Wang, Zhefang, Qin, Jie, Zhao, Jiangang, Li, Jiahui, Li, Dai, Popp, Marie, Popp, Felix, Alakus, Hakan, Kong, Bo, Dong, Qiongzhu, Nelson, Peter J., Zhao, Yue and Bruns, Christiane J. (2020). Inflammatory IFIT3 renders chemotherapy resistance by regulating post-translational modification of VDAC2 in pancreatic cancer. Theranostics, 10 (16). S. 7178 - 7193. LAKE HAVEN: IVYSPRING INT PUBL. ISSN 1838-7640

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide and effective therapy remains a challenge. IFIT3 is an interferon-stimulated gene with antiviral and pro-inflammatory functions. Our previous work has shown that high expression of IFIT3 is correlated with poor survival in PDAC patients who receive chemotherapy suggesting a link between IFIT3 and chemotherapy resistance in PDAC. However, the exact role and molecular mechanism of IFIT3 in chemotherapy resistance in PDAC has been unclear. Methods: A group of transcriptome datasets were downloaded and analyzed for the characterization of IFIT3 in PDAC. Highly metastatic PDAC cell line L3.6pl and patient-derived primary cell TBO368 were used and IFIT3 knockdown and the corresponding knockin cells were established for in vitro studies. Chemotherapy-induced apoptosis, ROS production, confocal immunofluorescence, subcellular fractionation, chromatin-immunoprecipitation, co-immunoprecipitation and mass spectrometry analysis were determined to further explore the biological role of IFIT3 in chemotherapy resistance of PDAC. Results: Based on PDAC transcriptome data, we show that IFIT3 expression is associated with the squamous molecular subtype of PDAC and an increase in inflammatory response and apoptosis pathways. We further identify a crucial role for IFIT3 in the regulation of mitochondria-associated apoptosis during chemotherapy. Knockdown of IFIT3 attenuates the chemotherapy resistance of PDAC cells to gemcitabine, paclitaxel, and FOLFIRINOX regimen treatments, independent of individual chemotherapy regimens. While IFIT3 overexpression was found to promote drug resistance. Co-immunoprecipitation identified a direct interaction between IFIT3 and the mitochondrial channel protein VDAC2, an important regulator of mitochondria-associated apoptosis. It was subsequently found that IFIT3 regulates the post-translational modification-O-GlcNAcylation of VDAC2 by stabilizing the interaction of VDAC2 with O-GlcNAc transferase. Increased O-GlcNAcylation of VDAC2 protected PDAC cells from chemotherapy induced apoptosis. Conclusions: These results effectively demonstrate a central mechanism by which IFIT3 expression can affect chemotherapy resistance in PDAC. Targeting IFIT3/VDAC2 may represent a novel strategy to sensitize aggressive forms of pancreatic cancer to conventional chemotherapy regimens.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wang, Zhefang UNSPECIFIED UNSPECIFIED UNSPECIFIED Qin, Jie UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhao, Jiangang UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Jiahui UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Dai UNSPECIFIED UNSPECIFIED UNSPECIFIED Popp, Marie UNSPECIFIED UNSPECIFIED UNSPECIFIED Popp, Felix UNSPECIFIED UNSPECIFIED UNSPECIFIED Alakus, Hakan UNSPECIFIED UNSPECIFIED UNSPECIFIED Kong, Bo UNSPECIFIED UNSPECIFIED UNSPECIFIED Dong, Qiongzhu UNSPECIFIED UNSPECIFIED UNSPECIFIED Nelson, Peter J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhao, Yue UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruns, Christiane J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-350667
DOI:	10.7150/thno.43093
Journal or Publication Title:	Theranostics
Volume:	10
Number:	16
Page Range:	S. 7178 - 7193
Date:	2020
Publisher:	IVYSPRING INT PUBL
Place of Publication:	LAKE HAVEN
ISSN:	1838-7640
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language REPEATS 3 IFIT3; DUCTAL ADENOCARCINOMA; O-GLCNACYLATION; INDUCED PROTEIN; INTERFERON; MECHANISMS; GEMCITABINE; SUBTYPES; SURVIVAL; BAK Multiple languages Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/35066