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.
Highlights
Elimination of cancer cells mainly relies on activation of the mitochondria-associated apoptosis pathway
Our results indicated that BCL-XL and MCL-1 safeguarded mitochondrial integrity in a functionally redundant manner, which necessitated dual BCL-XL/MCL-1 inhibition for efficient activation of the intrinsic apoptosis pathway
We investigated whether the hypertonicityinduced shift from BCL-XL/MCL-1 codependency to exclusive MCL-1 addiction (Fig. 2a–c) was due to changes in the network of BCL-2 family proteins
Summary
Elimination of cancer cells mainly relies on activation of the mitochondria-associated (intrinsic) apoptosis pathway. This cell death modality is tightly controlled by a complex network of BCL-2 family proteins. Targeting BCL-2-like proteins emerged as a therapeutic strategy and spurred development of “BH3 mimetics”[2]. Our previous work showed that cancer cells facing a hypertonic environment exhibited a lower threshold for MOMP induction[8,9,10]. We hypothesized that this could reflect hypertonicity-induced alterations in the BCL-2 family network. How hyperosmotic stress affects cancer cells has not been comprehensively investigated, but reports document enhanced cisplatin sensitivity, secretion of angiogenesis-promoting cytokines and upregulation of resistance- or metastasisassociated proteins[11,12,13,14]
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