TNF-alpha differentially modulates subunit levels of respiratory electron transport complexes of ER/PR plus ve/-ve breast cancer cells to regulate mitochondrial complex activity and tumorigenic potential
2021
Background: Tumor necrosis factor-α (TNF-α) is an immunostimulatory cytokine that is consistently high in the
breast tumor microenvironment (TME); however, its differential role in mitochondrial functions and cell survival in
ER/PR +ve and ER/PR −ve breast cancer cells is not well understood.
Methods: In the current study, we investigated TNF-α modulated mitochondrial proteome using high-resolution
mass spectrometry and identified the differentially expressed proteins in two different breast cancer cell lines, ER/PR
positive cell line; luminal, MCF-7 and ER/PR negative cell line; basal-like, MDA-MB-231 and explored its implication in
regulating the tumorigenic potential of breast cancer cells. We also compared the activity of mitochondrial
complexes, ATP, and ROS levels between MCF-7 and MDA-MB-231 in the presence of TNF-α. We used Tumor
Immune Estimation Resource (TIMER) webserver to analyze the correlation between TNF-α and mitochondrial
proteins in basal and luminal breast cancer patients. Kaplan-Meier method was used to analyze the correlation
between mitochondrial protein expression and survival of breast cancer patients.
Results: The proteome analysis revealed that TNF-α differentially altered the level of critical proteins of
mitochondrial respiratory chain complexes both in MCF-7 and MDA-MB-231, which correlated with differential
assembly and activity of mitochondrial ETC complexes. The inhibition of the glycolytic pathway in the presence of
TNF-α showed that glycolysis is indispensable for the proliferation and clonogenic ability of MDA-MB-231 cells (ER/
PR −ve) as compared to MCF-7 cells (ER/PR +ve). The TIMER database showed a negative correlation between the
expressions of TNF-α and key regulators of mitochondrial OXPHOS complexes in basal breast vs lobular carcinoma.
Conversely, patient survival analysis showed an improved relapse-free survival with increased expression of
identified proteins of ETC complexes and survival of the breast cancer patients.
Conclusion: The evidence presented in our study convincingly demonstrates that TNF-α regulates the survival and
proliferation of aggressive tumor cells by modulating the levels of critical assembly factors and subunits involved in
mitochondrial respiratory chain supercomplexes organization and function. This favors the rewiring of
mitochondrial metabolism towards anaplerosis to support the survival and proliferation of breast cancer cells.
Collectively, the results strongly suggest that TNF-α differentially regulates metabolic adaptation in ER/PR +ve (MCF-
7) and ER/PR −ve (MDA-MB-231) cells by modulating the mitochondrial supercomplex assembly and activity.
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