Breast Cancer Associated Gene 2 (BCA2) is a novel RING-finger ubiquitin E3 ligase that is overexpressed in >50% of breast tumors. AMPK is the master regulator of cellular energy homeostasis that has recently emerged as a promising molecular target in the treatment of breast and other cancers. Although the FDA- approved, AMPK activating, anti-diabetic drug metformin is in Phase III clinical trials, the benefit of AMPK activation remains controversial in various cancer types, due to lack of detailed mechanistic studies. We have found that metformin treatment of breast cancer cells induces BCA2 expression that then feedback inhibits the induced AMPK activation. Our discovery of this novel BCA2-AMPK regulatory pathway could explain why patients have various responses to metformin therapies, and suggests that metformin therapy when combined with a BCA2 inhibitor may be a more effective breast cancer treatment strategy than metformin alone. I In the current study, we hypothesize: (i) Metformin-mediated AMPK activation in human breast cancer cells triggers two conflicting signaling pathways: the well-known cancer-preventive/ tumor-suppressing signal via mTOR inhibition and the less-known cancer-survival feedback pathway via induction of the E3 ligase BCA2 activity that leads to degradation of a potential AMPK-activating kinase;(ii) Inhibition of BCA2-mediated feedback loop will increase the breast cancer-preventive effect of metformin. To test our hypotheses, we propose to study the role of BCA2 in metformin-induced, AMPK-mediated survival feedback loop in breast cancer cells (Aim 1), to identify the BCA2 substrate, a potential AMPK-activating kinase, and to study its function in metformin-induced survival feedback loop (Aim 2), and finally, to determine whether inhibition of BCA2 activity could increase breast cancer-preventive effect of metformin in mice (Aim 3). The successful completion of this project will significantly improve understanding of the molecular mechanisms of clinical metformin efficacy, help interpret the existing clinical data about various metformin efficacies in different cancer patients, and provide a scientific basis for designing rationalized metformin-based cancer prevention clinical trials. Our study could move the metformin research beyond the current correlative stages and establish, for the first time, detailed, mechanistic pathways that link tumor tissue BCA2 status to metformin efficacy and to changes that alter cancer incidence. This innovative proposal will: (i) study a previously unknown key component involved in the metformin- induced cancer cell survival feedback loop, the E3 ligase BCA2 that causes degradation of a potential tumor- suppressing AMPK-activating kinase;(ii) seek to shift the paradigms of current metformin research and its clinical use by means of a novel rationale and methodology for combining metformin with an inhibitor of BCA2 or AKT to increase the efficacy of metformin in breast cancer cells containing high levels of BCA2-mediated AMPK-inhibitory signal.
This application tests the novel hypotheses that (i) the FDA-approved, AMPK activating, anti-diabetic drug metformin triggers two conflicting signaling pathways in human breast cancer cells: the well-known cancer- preventive/ tumor-suppressing signal via mTOR inhibition and the less-known cancer-survival feedback pathway via induction of the E3 ligase BCA2 activity that leads to degradation of a potential AMPK-activating kinase, and (ii) Inhibition of BCA2-mediated feedback loop will increase the breast cancer-preventive effect of metformin. The completion of the proposed study will move the metformin research beyond the current correlative stages and establish, for the first time, detailed, mechanistic pathways that link tumor tissue BCA2 status to metformin efficacy and to changes that alter cancer incidence.
|Schmitt, Sara M; Neslund-Dudas, Christine; Shen, Min et al. (2016) Involvement of ALAD-20S Proteasome Complexes in Ubiquitination and Acetylation of Proteasomal Î±2 Subunits. J Cell Biochem 117:144-51|
|Mohammad, Ramzi M; Muqbil, Irfana; Lowe, Leroy et al. (2015) Broad targeting of resistance to apoptosis in cancer. Semin Cancer Biol 35 Suppl:S78-103|
|Arkwright, Richard T; Deshmukh, Rahul; Adapa, Nikhil et al. (2015) Lessons from Nature: Sources and Strategies for Developing AMPK Activators for Cancer Chemotherapeutics. Anticancer Agents Med Chem 15:657-71|
|Deshmukh, Rahul R; Dou, Q Ping (2015) Proteasome inhibitors induce AMPK activation via CaMKKÎ² in human breast cancer cells. Breast Cancer Res Treat 153:79-88|
|Farshi, Pershang; Deshmukh, Rahul R; Nwankwo, Joseph O et al. (2015) Deubiquitinases (DUBs) and DUB inhibitors: a patent review. Expert Opin Ther Pat 25:1191-208|
|Block, Keith I; Gyllenhaal, Charlotte; Lowe, Leroy et al. (2015) Designing a broad-spectrum integrative approach for cancer prevention and treatment. Semin Cancer Biol 35 Suppl:S276-304|
|Zhang, Zhongyu; Bi, Caifeng; Fan, Yuhua et al. (2015) L-Ornithine Schiff base-copper and -cadmium complexes as new proteasome inhibitors and apoptosis inducers in human cancer cells. J Biol Inorg Chem 20:109-21|
|Dou, Q Ping; Zonder, Jeffrey A (2014) Overview of proteasome inhibitor-based anti-cancer therapies: perspective on bortezomib and second generation proteasome inhibitors versus future generation inhibitors of ubiquitin-proteasome system. Curr Cancer Drug Targets 14:517-36|
|Cheriyan, Vino T; Wang, Ying; Muthu, Magesh et al. (2014) Disulfiram suppresses growth of the malignant pleural mesothelioma cells in part by inducing apoptosis. PLoS One 9:e93711|
|Lu, Li; Shi, Wenli; Deshmukh, Rahul R et al. (2014) Tumor necrosis factor-Î± sensitizes breast cancer cells to natural products with proteasome-inhibitory activity leading to apoptosis. PLoS One 9:e113783|
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