Theranostics 2020; 10(16):7178-7192. doi:10.7150/thno.43093 This issue Cite

Research Paper

Inflammatory IFIT3 renders chemotherapy resistance by regulating post-translational modification of VDAC2 in pancreatic cancer

Zhefang Wang1, Jie Qin1, Jiangang Zhao1,2, Jiahui Li1, Dai Li1,3, Marie Popp1, Felix Popp1, Hakan Alakus1, Bo Kong4, Qiongzhu Dong5, Peter J. Nelson6, Yue Zhao1✉, Christiane J. Bruns1✉

1. Department of General, Visceral, Tumor and Transplantation Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany.
2. Department of General, Visceral und Vascular Surgery, Ludwig-Maximilian-University (LMU), 81377 Munich, Germany.
3. Department of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, PR China.
4. Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
5. Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
6. Medizinische Klinik und Poliklinik IV, University of Munich, Munich, Germany.

Citation:
Wang Z, Qin J, Zhao J, Li J, Li D, Popp M, Popp F, Alakus H, Kong B, Dong Q, Nelson PJ, Zhao Y, Bruns CJ. Inflammatory IFIT3 renders chemotherapy resistance by regulating post-translational modification of VDAC2 in pancreatic cancer. Theranostics 2020; 10(16):7178-7192. doi:10.7150/thno.43093. https://www.thno.org/v10p7178.htm
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Abstract

Graphic 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.

Keywords: PDAC, Chemotherapy resistance, IFIT3, VDAC2, post-translational modification


Citation styles

APA
Wang, Z., Qin, J., Zhao, J., Li, J., Li, D., Popp, M., Popp, F., Alakus, H., Kong, B., Dong, Q., Nelson, P.J., Zhao, Y., Bruns, C.J. (2020). Inflammatory IFIT3 renders chemotherapy resistance by regulating post-translational modification of VDAC2 in pancreatic cancer. Theranostics, 10(16), 7178-7192. https://doi.org/10.7150/thno.43093.

ACS
Wang, Z.; Qin, J.; Zhao, J.; Li, J.; Li, D.; Popp, M.; Popp, F.; Alakus, H.; Kong, B.; Dong, Q.; Nelson, P.J.; Zhao, Y.; Bruns, C.J. Inflammatory IFIT3 renders chemotherapy resistance by regulating post-translational modification of VDAC2 in pancreatic cancer. Theranostics 2020, 10 (16), 7178-7192. DOI: 10.7150/thno.43093.

NLM
Wang Z, Qin J, Zhao J, Li J, Li D, Popp M, Popp F, Alakus H, Kong B, Dong Q, Nelson PJ, Zhao Y, Bruns CJ. Inflammatory IFIT3 renders chemotherapy resistance by regulating post-translational modification of VDAC2 in pancreatic cancer. Theranostics 2020; 10(16):7178-7192. doi:10.7150/thno.43093. https://www.thno.org/v10p7178.htm

CSE
Wang Z, Qin J, Zhao J, Li J, Li D, Popp M, Popp F, Alakus H, Kong B, Dong Q, Nelson PJ, Zhao Y, Bruns CJ. 2020. Inflammatory IFIT3 renders chemotherapy resistance by regulating post-translational modification of VDAC2 in pancreatic cancer. Theranostics. 10(16):7178-7192.

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