BCL2 and BCL(X)L selective inhibitors decrease mitochondrial ATP production in breast cancer cells and are...

Area of Science:

• Oncology
• Cancer Metabolism
• Mitochondrial Bioenergetics

Background:

• Cancer cells exhibit metabolic plasticity, utilizing either glycolysis or mitochondrial oxidative phosphorylation (OXPHOS).
• Estrogen receptor-positive (ER+) breast cancer relies on OXPHOS, while triple-negative breast cancer (TNBC) favors glycolysis.
• BCL2 proteins are crucial regulators of apoptosis and cellular bioenergetics, and are overexpressed in breast cancer.

Purpose of the Study:

• To investigate the impact of BCL2 and BCL(XL) selective inhibitors (Venetoclax and WEHI-539) on mitochondrial bioenergetics and cell death in breast cancer.
• To explore the potential for synthetic lethality by combining BCL2/BCL(XL) inhibition with glycolysis inhibition.

Main Methods:

• Utilized single-cell imaging with a FRET-based mitochondrial ATP sensor to assess ATP production.
• Employed quantitative confocal microscopy to evaluate mitochondrial network length and dynamics.
• Tested the synergistic effects of BCL2/BCL(XL) inhibitors combined with 2-deoxy-D-glucose (glycolysis inhibitor) in ER+ and TNBC cells, including 3D sphere cultures.

Main Results:

• Venetoclax and WEHI-539 reduced mitochondrial ATP production in MCF7 cells without inducing cell death.
• Lower inhibitor concentrations decreased mitochondrial network length and dynamics.
• Combination therapy with glycolysis inhibitors synergistically impaired cellular bioenergetics and abolished clonogenic potential in both ER+ and TNBC cells.

Conclusions:

• BCL2 antagonists significantly impact cancer cell metabolism independently of their cell death-inducing properties.
• A synthetic lethality strategy combining BCL2/BCL(XL) inhibition with glycolysis inhibition shows promise for breast cancer therapy.
• Targeting both OXPHOS and glycolysis pathways offers a novel therapeutic approach for diverse breast cancer subtypes.