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Regulation of metformin response by breast cancer associated gene 2
Daniela Buac1, Fathima R Kona1, Arun K Seth2
1Department of Oncology and Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI.
Abstract:
Adenosine monophosphate-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis, has emerged as a promising molecular target in the prevention of breast cancer. Clinical trials using the United States Food and Drug Administration (FDA)-approved, AMPK-activating, antidiabetic drug metformin are promising in this regard, but the question of why metformin is protective for some women but not others still remains. Breast cancer associated gene 2 (BCA2/Rabring7/RNF115), a novel Really Interesting New Gene (RING) finger ubiquitin E3 ligase, is overexpressed in >50% of breast tumors. Herein, we report that BCA2 is an endogenous inhibitor of AMPK activation in breast cancer cells and that BCA2 inhibition increases the efficacy of metformin. BCA2 overexpression inhibited both basal and inducible Thr172 phosphorylation/activation of AMPKα1, while BCA2-specific small interfering RNA (siRNA) enhanced phosphorylated AMPKα1 (pAMPKα1). The AMPK-suppressive function of BCA2 requires its E3 ligase-specific RING domain, suggesting that BCA2 targets some protein controlling (de)phosphorylation of AMPKα1 for degradation. Activation of AMPK by metformin triggered a growth inhibitory signal but also increased BCA2 protein levels, which correlated with AKT activation and could be curbed by an AMPK inhibitor, suggesting a potential feedback mechanism from pAMPKα1 to pAkt to BCA2. Finally, BCA2 siRNA, or inhibition of its upstream stabilizing kinase AKT, increased the growth inhibitory effect of metformin in multiple breast cancer cell lines, supporting the conclusion that BCA2 weakens metformin's efficacy. Our data suggest that metformin in combination with a BCA2 inhibitor may be a more effective breast cancer treatment strategy than metformin alone.
Insights
Breast cancer drug metformin works better when combined with a BCA2 inhibitor. BCA2 (Breast Cancer Associated Gene 2) protein blocks metformin
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of cellular energy and a potential target for breast cancer prevention.
- Metformin, an FDA-approved drug, activates AMPK and shows promise in clinical trials, but its efficacy varies among individuals.
- Breast cancer associated gene 2 (BCA2), a ubiquitin E3 ligase, is overexpressed in many breast tumors and may influence treatment response.
Purpose of the Study:
- To investigate the role of BCA2 as an endogenous inhibitor of AMPK activation in breast cancer cells.
- To determine if inhibiting BCA2 can enhance the efficacy of metformin in breast cancer treatment.
- To elucidate the molecular mechanisms underlying the interaction between BCA2, AMPK, and metformin.
Main Methods:
- Utilized small interfering RNA (siRNA) to specifically inhibit BCA2 expression in breast cancer cell lines.
- Assessed AMPK activation by measuring Thr172 phosphorylation (pAMPKα1) under various treatment conditions.
- Investigated the role of BCA2's E3 ligase activity and its interaction with AKT signaling pathway.
Main Results:
- BCA2 overexpression suppressed both basal and metformin-induced AMPK activation, while BCA2 siRNA enhanced pAMPKα1 levels.
- Metformin treatment increased BCA2 protein levels, suggesting a feedback loop involving AKT activation.
- Inhibition of BCA2 or AKT significantly potentiated the growth-inhibitory effects of metformin in breast cancer cells.
Conclusions:
- BCA2 acts as an endogenous inhibitor of AMPK activation and reduces metformin's efficacy in breast cancer.
- Targeting BCA2, potentially through inhibition, could overcome metformin resistance and improve treatment outcomes.
- Combining metformin with a BCA2 inhibitor represents a promising therapeutic strategy for breast cancer treatment.
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