Inhibition of DGAT for the treatment of cancer
Dysregulated fat metabolism is an established hallmark of cancer cells. However, the disruption of lipid homeostasis in cancer cells remains an elusive target for therapy. Tumor cells acquire abundant fats for rapid cell growth, but how they avoid toxicity from such loading is unknown. An answer to this question may allow leveraging of such insight to introduce a vulnerability to tumor cells and thus an effective strategy to treat cancer.
Diacylglycerol-acyltransferase (DGAT) regulates the final and committed step for triglyceride synthesis. There are two known isoforms of the enzyme, DGAT 1 and DGAT 2. Due to their well-established role in lipid metabolism, several isoform-specific inhibitors have been the focus of industry sponsored clinical pipelines for various metabolic diseases, such as obesity, dyslipidemia, and fatty liver disease. However, the effects of DGAT inhibition in various cancer types are poorly understood.
Researchers at The Ohio State University, led by Dr. Deliang Guo, have discovered a novel therapeutic strategy targeting DGAT in cancer. They have demonstrated DGAT plays a critical role in regulating lipid homeostasis and protecting cancer cells from oxidative damage induced by excess fatty acids. DGAT isoforms are differentially regulated in different cancer types, and inhibiting DGAT induces dramatic cell apoptosis and reduction of tumor growth in vitro and in vivo. Importantly, examination of patient samples demonstrated high levels of DGAT are associated with poor patient survival. Dr. Guo's studies uncover previously unrecognized molecular mechanisms regulating lipid homeostasis in cancer and offer a promising new approach for the treatment of glioblastoma and other cancer types, such as hepatocellular carcinoma.
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