Knoll, Gertrud and Riffelsberger, Petra and Raats, Danielle and Kranenburg, Onno and Ehrenschwender, Martin (2020) NOXA-dependent contextual synthetic lethality of BCL-XL inhibition and "osmotic reprogramming" in colorectal cancer. CELL DEATH & DISEASE, 11 (4): 257. ISSN 2041-4889,
Full text not available from this repository. (Request a copy)Abstract
A sophisticated network of BCL-2 family proteins regulates the mitochondria-associated (intrinsic) apoptosis pathway. Antiapoptotic members such as BCL-XL or MCL-1 safeguard the outer mitochondrial membrane and prevent accidental cell death in a functionally redundant and/or compensatory manner. However, BCL-XL/MCL-1-mediated "dual apoptosis protection" also impairs response of cancer cells to chemotherapy. Here, we show that hyperosmotic stress in the tumor environment abrogates dual BCL-XL/MCL-1 protection. Hypertonicity triggers upregulation of NOXA and loss of MCL-1 and thereby enforces exclusive BCL-XL addiction. Concomitant targeting of BCL-XL is sufficient to unlock the intrinsic apoptosis pathway in colorectal cancer cells. Functionally, "osmotic reprogramming" of the tumor environment grants contextual synthetic lethality to BCL-XL inhibitors in dually BCL-XL/MCL-1-protected cells. Generation of contextual synthetic lethality through modulation of the tumor environment could perspectively boost efficacy of anticancer drugs.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | INDUCED CELL-DEATH; HYPEROSMOTIC STRESS; MELANOMA-CELLS; APOPTOTIC RESPONSE; MCL-1; PROTEINS; FAMILY; BAX; INDUCTION; BIM; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Medizinische Mikrobiologie und Hygiene |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 26 Mar 2021 10:03 |
| Last Modified: | 26 Mar 2021 10:03 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44729 |
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