TY - JOUR
T1 - NOXA-dependent contextual synthetic lethality of BCL-XL inhibition and “osmotic reprogramming” in colorectal cancer
AU - Knoll, Gertrud
AU - Riffelsberger, Petra
AU - Raats, Danielle
AU - Kranenburg, Onno
AU - Ehrenschwender, Martin
N1 - Funding Information:
We thank Richard Youle (National Institutes of Health, Bethesda, USA), Xu Luo (Nebraska Medical Center, Nebraska, USA) and Hamsa Puthalakath (La Trobe University, Bundoora, Australia) for providing HCT116 knockout cell lines. M.E. is supported by grants from the Universitätsstiftung Helga und Erwin Hartl and the Universitätsstiftung Angela Schötz-Keilholz.
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85083808263&partnerID=8YFLogxK
U2 - 10.1038/s41419-020-2446-8
DO - 10.1038/s41419-020-2446-8
M3 - Article
C2 - 32312973
AN - SCOPUS:85083808263
VL - 11
SP - 1
EP - 11
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 4
M1 - 257
ER -