Cancer Biol Ther. 2013 Sep 6;14(11). [Epub ahead of print]
Omega-3 polyunsaturated fatty acid promotes the inhibition of glycolytic enzymes and mTOR signaling by regulating the tumor suppressor LKB1.
Andrade-Vieira R, Han JH, Marignani PA.
Department of Biochemistry and Molecular Biology; Faculty of Medicine; Dalhousie University; Halifax, NS Canada.
The omega-3 polyunsaturated fatty acids (ω3PUFAs) are a class of lipids biologically effective for the treatment of inflammatory disorders, cardiovascular disease and cancer. Patients consuming a high dietary intake of ω3PUFAs have shown a low incidence of metabolic disorders, including cancer. Although the effects of ω3PUFAs intake was shown to be involved in the prevention and treatment of these diseases, the underlying molecular mechanisms involved are not well understood. Here, we show that ω3PUFA, docosahexaenoic acid (DHA) enhanced the tumor suppressor function of LKB1. We observed that when LKB1 expressing cells are treated with DHA, there is an increase in LKB1 activity leading to phosphorylation of AMPK and inhibition of mTOR signaling. Abrogation of LKB1 in MCF-7 by siRNA reversed this phenotype. Furthermore, cellular metabolism was altered and ATP levels were reduced in response to DHA treatment, which was further attenuated in cells expressing LKB1. More importantly, in mammary epithelial cells expressing LKB1, the rate of glycolysis was decreased as a result of diminished expression of glycolytic enzymes. Functionally, these events lead to a decrease in the migration potential of these cells. Overall, our discovery shows for the first time that LKB1 function is enhanced in response to ω3PUFA treatment, thereby regulating cell metabolism.
DHA, LDH-A, LKB1, aerobic glycolysis, cancer, cell metabolism, glycolytic enzymes, hexokinase, mTOR signaling, omega-3 PUFA
[PubMed – as supplied by publisher]
J Clin Invest. 2013 Sep 3;123(9):3685-92. doi: 10.1172/JCI69741. Epub 2013 Sep 3.
Targeting lactate metabolism for cancer therapeutics.
Doherty JR, Cleveland JL.
Lactate, once considered a waste product of glycolysis, has emerged as a critical regulator of cancer development, maintenance, and metastasis. Indeed, tumor lactate levels correlate with increased metastasis, tumor recurrence, and poor outcome. Lactate mediates cancer cell intrinsic effects on metabolism and has additional non-tumor cell autonomous effects that drive tumorigenesis. Tumor cells can metabolize lactate as an energy source and shuttle lactate to neighboring cancer cells, adjacent stroma, and vascular endothelial cells, which induces metabolic reprogramming. Lactate also plays roles in promoting tumor inflammation and in functioning as a signaling molecule that stimulates tumor angiogenesis. Here we review the mechanisms of lactate production and transport and highlight emerging evidence indicating that targeting lactate metabolism is a promising approach for cancer therapeutics.
[PubMed – in process]
[Available on 2014/1/1]
Curr Protoc Pharmacol. 2013 Jun;Chapter 14:Unit 14.25. doi: 10.1002/0471141755.ph1425s61.
Overview of cancer stem cells (CSCs) and mechanisms of their regulation: implications for cancer therapy.
Bao B, Ahmad A, Azmi AS, Ali S, Sarkar FH.
Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
The identification of small subpopulations of cancer stem cells (CSCs) from blood mononuclear cells in human acute myeloid leukemia (AML) in 1997 was a landmark observation that recognized the potential role of CSCs in tumor aggressiveness. Two critical properties contribute to the functional role of CSCs in the establishment and recurrence of cancerous tumors: their capacity for self-renewal and their potential to differentiate into unlimited heterogeneous populations of cancer cells. These findings suggest that CSCs may represent novel therapeutic targets for the treatment and/or prevention of tumor progression, since they appear to be involved in cell migration, invasion, metastasis, and treatment resistance-all of which lead to poor clinical outcomes. The identification of CSC-specific markers, the isolation and characterization of CSCs from malignant tissues, and targeting strategies for the destruction of CSCs provide a novel opportunity for cancer research. This overview describes the potential implications of several common CSC markers in the identification of CSC subpopulations that are restricted to common malignant diseases, e.g., leukemia, and breast, prostate, pancreatic, and lung cancers. The role of microRNAs (miRNAs) in the regulation of CSC function is also discussed, as are several methods commonly used in CSC research. The potential role of the antidiabetic drug metformin- which has been shown to have effects on CSCs, and is known to function as an antitumor agent-is discussed as an example of this new class of chemotherapeutics.
© 2013 by John Wiley & Sons, Inc.