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

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.

• Authors: Yuan Xu, Deborah R Surman, Laurence Diggs, Sichuan Xi, Shaojian Gao, Devikala Gurusamy, Kaitlin McLoughlin, Justin Drake, Paul Feingold, Kate Brown, Danny Wangsa, Darawalee Wangsa, Xi Zhang, Thomas Ried, Jeremy L Davis, Jonathan Hernandez, Chuong D Hoang, Rhonda F Souza, David S Schrump, R Taylor Ripley
• Journal: Oncogene (Oncogene) Vol. 39 Issue 4 Pg. 877-890 (01 2020) ISSN: 1476-5594 [Electronic] England
• PMID: 31570787 (Publication Type: Journal Article)

Chemical References

• Bile Acids and Salts
• Gastrointestinal Agents
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Cytochromes c

Topics

• Apoptosis
• Barrett Esophagus (drug therapy, genetics, metabolism, pathology)
• Bile Acids and Salts (pharmacology)
• Carcinogenesis (chemically induced, genetics, metabolism, pathology)
• Cell Line
• Cell Membrane Permeability
• Cytochromes c (metabolism)
• DNA Damage
• Esophageal Neoplasms (drug therapy, genetics, metabolism, pathology)
• Esophagus (drug effects, metabolism, pathology)
• Gastrointestinal Agents (pharmacology)
• Humans
• Mitochondria (drug effects, metabolism, pathology)
• Myeloid Cell Leukemia Sequence 1 Protein (metabolism)
• Signal Transduction