FASNating Targets of Metformin in Breast Cancer Stem-Like Cells

Abstract

Diabetes, Breast Cancer, and MetforminEmerging data suggest that metformin treatment is associated with reduced breast cancer incidence and mortality for individuals with type II diabetes [7,6,17]. For years, many studies have been done to investigate the possible direct and indirect effects of metformin on cancers of various origins. In diabetic patients, metformin improves metabolic function by promoting muscle glucose uptake and lowering hepatic gluconeogenesis [14,15,36]. In cultured cancer and normal cells, metformin has pleiotropic effects, including decreasing mitochondrial electron transport complex I activity, increasing the cellular AMP to ATP ratio, and activating the AMPK signaling pathway. The consequence of this is reduced protein translation, DNA synthesis, and cell proliferation. In isolated cancer stem-like cells (CSC), metformin's targets range from inflammation [13], to micro-RNAs [1], to the synthesis of nucleotide triphosphates [16]. The diversity of responses elicited by metformin from different tissues and from the specific cell types within those tissues suggests that metformin may be a valuable therapeutic for the treatment of a variety of cancers at many stages of tumor progression. Indeed, scores of clinical trials aiming to investigate the therapeutic effects of metformin for patients with cancer are either planned or ongoing. For breast cancer, large trials are open for patients with early-stage disease (NCT01101438) and metastatic disease (NCT01310231). The results of these trials are highly anticipated and will likely answer many lingering questions about the efficacy of metformin against cancer in nondiabetic patients. Short-term trials have also been conducted to evaluate the effects of metformin on breast tumor cell proliferation (NCT00897884) and tumor cell metabolism (NCT01266486).In this issue, Wahdan-Alaswad et al. demonstrate that in ER/PR/HER2-negative (triple negative (TN)) breast cancer cells metformin treatment targets fatty acid synthase (FASN) through a miR193b-dependent mechanism. Specifically, in TN breast cancer cells, metformin upregulated miR193b, which directly targeted the FASN mRNA resulting in decreased FASN protein levels. This was associated with reduced proliferation and increased apoptosis. Gene expression profiling also revealed changes in other metabolic enzymes, including members of the cholesterol biosynthesis pathway, suggesting that metformin may impact cancer cell lipid metabolism networks at multiple nodes. One limitation of this study is that the levels of cellular fatty acids were not quantified. Presumably, the amounts of de novo synthesized fatty acids correlate with the levels of FASN protein. In cancer cells, FASN expression is regulated by the HER2/Neu and PI3K signaling pathways, steroid hormones, and genomic amplification [20,34,37,42]; however, the spectrum of fatty acid products and the kinetics of the FASN reaction can be altered by effector proteins [21,32]. Interestingly, the effects of metformin on miR193b and FASN were only observe...

AMPK activation by AICAR sensitizes prostate cancer cells to radiotherapy

“…We also observed the phosphorylation of ACC in response to AICAR at concentrations used in this study. Furthermore, metformin decreased FASN protein levels in breast cancer cells [49] and the FASN inhibitor orlistat up-regulated AMPK activity in lung cancer cells [50]. This demonstrates the critical role of fatty acid metabolism in cellular energy production and suggests an important interaction between AMPK and FASN.…”

Orlistat Resensitizes Sorafenib-Resistance in Hepatocellular Carcinoma Cells through Modulating Metabolism

“…Several studies have reported that FASN expression positively correlates to cancer stages, including prostate cancer [ 8 ], renal cancer [ 9 ], and colorectal cancer [ 10 ]. Moreover, FASN inhibition can decrease the cancer cell stemness in breast cancer [ 11 , 12 ] and glioma [ 13 ]. Interestingly, it has been shown that sorafenib-resistant HCC cells demonstrate more characteristics of cancer stem cells than their parental counterparts [ 14 , 15 ].…”