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Bile acid-induced “Minority MOMP” promotes esophageal carcinogenesis while maintaining apoptotic resistance via Mcl-1

Oncogene volume 39, pages 877–890 (2020)Cite this article

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Abstract

Barrett’s esophagus (BE) is associated with reflux and is implicated the development of esophageal adenocarcinoma (EAC). Apoptosis induces cell death through mitochondrial outer membrane permeabilization (MOMP), which is considered an irreversible step in apoptosis. Activation of MOMP to levels that fail to reach the apoptotic threshold may paradoxically promote cancer—a phenomenon called “Minority MOMP.” We asked whether reflux-induced esophageal carcinogenesis occurred via minority MOMP and whether compensatory resistance mechanisms prevented cell death during this process. We exposed preneoplastic, hTERT-immortalized Barrett’s cell, CP-C and CP-A, to the oncogenic bile acid, deoxycholic acid (DCA), for 1 year. Induction of minority MOMP was tested via comet assay, CyQuant, annexin V, JC-1, cytochrome C subcellular localization, caspase 3 activation, and immunoblots. We used bcl-2 homology domain-3 (BH3) profiling to test the mitochondrial apoptotic threshold. One-year exposure of Barrett’s cells to DCA induced a malignant phenotype noted by clone and tumor formation. DCA promoted minority MOMP noted by minimal release of cytochrome C and limited caspase 3 activation, which resulted in DNA damage without apoptosis. Upregulation of the antiapoptotic protein, Mcl-1, ROS generation, and NF-κB activation occurred in conjunction with minority MOMP. Inhibition of ROS blocked minority MOMP and Mcl-1 upregulation. Knockdown of Mcl-1 shifted minority MOMP to complete MOMP as noted by dynamic BH3 profiling and increased apoptosis. Minority MOMP contributes to DCA induced carcinogenesis in preneoplastic BE. Mcl-1 provided a balance within the mitochondria that induced resistance complete MOMP and cell death. Targeting Mcl-1 may be a therapeutic strategy in EAC.

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Acknowledgements

The authors thank Dr Chuan-Yuan Li, Duke University, for the kind gift of the caspase 3 reporter plasmid and Dr Jeremy Ryan and Dr Anthony Letai for BH3 profiling support.

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Authors and Affiliations

  1. Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA

    Yuan Xu, Deborah R. Surman, Laurence Diggs, Sichuan Xi, Shaojian Gao, Kaitlin McLoughlin, Justin Drake, Paul Feingold, Kate Brown, Jeremy L. Davis, Jonathan Hernandez, Chuong D. Hoang, David S. Schrump & R. Taylor Ripley

  2. Division of General Thoracic Surgery, Michael E. DeBakey Department of General Surgery, Baylor College of Medicine, Houston, TX, USA

    Deborah R. Surman & R. Taylor Ripley

  3. Surgery Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA

    Devikala Gurusamy

  4. Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA

    Danny Wangsa, Darawalee Wangsa & Thomas Ried

  5. Department of Medicine, Center for Esophageal Diseases, Baylor University Medical Center and Center for Esophageal Research, Baylor Scott and White Research Institute, Dallas, TX, USA

    Xi Zhang & Rhonda F. Souza

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Correspondence to R. Taylor Ripley.

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Xu, Y., Surman, D.R., Diggs, L. et al. Bile acid-induced “Minority MOMP” promotes esophageal carcinogenesis while maintaining apoptotic resistance via Mcl-1. Oncogene 39, 877–890 (2020). https://doi.org/10.1038/s41388-019-1029-6

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