Tumor cells adapt to their high metabolic state by increasing energy production. To this end, current efforts in molecular cancer therapeutics have been focused on signaling pathways that modulate cellular metabolism. However, targeting such signaling pathways is challenging due to heterogeneity of tumors and recurrent oncogenic mutations. A critical need remains to develop antitumor drugs that target tumor specific pathways. Here, we discuss an energy metabolic pathway that is preferentially activated in several cancers as a potential target for molecular cancer therapy. In vitro studies have revealed that many cancer cells synthesize guanosine triphosphate (GTP), via the de novo purine nucleotide synthesis pathway by upregulating the rate limiting enzyme of this pathway, inosine monophosphate dehydrogenase (IMPDH). Non-proliferating cells use an alternative purine nucleotide synthesis pathway, the salvage pathway, to synthesize GTP. These observations pose IMPDH as a potential target to suppress tumor cell growth. The IMPDH inhibitor, mycophenolate mofetil (MMF), is an FDA-approved immunosuppressive drug. Accumulating evidence shows that, in addition to its immunosuppressive effects, MMF also has antitumor effects via IMPDH inhibition in vitro and in vivo. Here, we review the literature on IMPDH as related to tumorigenesis and the use of MMF as a potential antitumor drug. 1. Introduction Metabolic regulation in tumors is different from resting adult tissues. Tumor cells increase synthesis of proteins, lipids, and nucleotides to adapt to their rapid proliferation. Nearly, a century ago, Dr. Otto Warburg first described the altered metabolism of cancer cells, known as the “Warburg effect.” The Warburg effect is the observation that the energy needed by tumor cells is mainly produced through high rates of glycolysis followed by lactic acid fermentation in the cytosol, as opposed to the low rate of glycolysis followed by pyruvate oxidation in the mitochondria of nonmalignant cells. The relationship between tumor and metabolism has just recently been a major focus of cancer biology. Growing evidence supports a pivotal role for oncogenic mutations and the resultant altered signaling pathways that dramatically change cell metabolism. For example, phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) signaling pathways are established oncogenic drivers in a variety of cancers [1]. These signaling pathways lead to increased glucose uptake and many anabolic processes, such as lipid biosynthesis and protein and nucleotide synthesis [2].
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