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NOXA-dependent contextual synthetic lethality of BCL-XL inhibition and "osmotic reprogramming" in colorectal cancer
Gertrud Knoll1, Petra Riffelsberger1, Danielle Raats2
1Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Franz-Josef-Strauss-Allee 11, 93053, Regensburg, Germany.
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.
Insights
Hyperosmotic stress in tumors overcomes dual apoptosis protection by BCL-XL and MCL-1 proteins. This strategy sensitizes cancer cells to BCL-XL inhibitors, enhancing chemotherapy effectiveness.
Area of Science:
- Molecular Biology
- Cancer Biology
- Cell Death Pathways
Background:
- The BCL-2 protein family critically regulates intrinsic apoptosis.
- Anti-apoptotic proteins BCL-XL and MCL-1 provide redundant protection against cell death.
- This dual protection hinders cancer chemotherapy efficacy.
Purpose of the Study:
- To investigate if hyperosmotic stress can overcome dual BCL-XL/MCL-1-mediated apoptosis resistance.
- To explore the potential of modulating the tumor microenvironment to enhance cancer therapy.
Main Methods:
- Induction of hyperosmotic stress in colorectal cancer cells.
- Analysis of BCL-2 family protein expression and apoptosis.
- Assessment of sensitivity to BCL-XL inhibitors.
Main Results:
- Hyperosmotic stress led to NOXA upregulation and MCL-1 downregulation.
- This abrogated dual protection, enforcing BCL-XL dependency.
- Targeting BCL-XL in hypertonic conditions induced apoptosis in cancer cells.
Conclusions:
- Tumor microenvironment modulation via hypertonicity can create synthetic lethality for BCL-XL inhibitors.
- "Osmotic reprogramming" offers a novel strategy to enhance anticancer drug efficacy.
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