This complex consists of the core components mTOR, a serine/threonine protein kinase, Raptor (regulatory protein associated with mTOR) and mLST8 (mammalian lethal with Sec13 protein 8) [132,133]

This complex consists of the core components mTOR, a serine/threonine protein kinase, Raptor (regulatory protein associated with mTOR) and mLST8 (mammalian lethal with Sec13 protein 8) [132,133]. metabolic flexibility, like gluconeogenesis enzymes. Moreover, a ON123300 conceptual framework for potential therapies targeting metabolically flexible cancer cells is presented. biosynthesis pathway by phosphorylation of acetyl-CoA carboxylase while it enhances fatty acid oxidation. Importantly, AMPK activates autophagy, by direct phosphorylation of ULK1 [130]. In the liver, AMPK inhibits gluconeogenesis which is an anabolic, energy consuming process, via phosphorylation and nuclear exclusion of the CREB coactivator TORC2 (transducer of regulated CREB activity 2, also known as CRTC2) [131]. Mammalian target of rapamycin complex 1 (mTORC1) is another important signaling node influenced by glucose but also by amino acid levels. This complex consists of the core components mTOR, a serine/threonine protein kinase, Raptor (regulatory protein associated with ON123300 mTOR) and mLST8 (mammalian lethal with Sec13 protein 8) [132,133]. High levels of glucose or high intracellular concentration of leucine activate mTORC1. mTORC1 controls the balance between anabolic and catabolic pathways in response to nutrient availability by regulating the biosynthesis of macromolecules while suppressing catabolic pathways such as autophagy (reviewed in [133]). The glycolytic intermediate dihydroxyacetone phosphate has just recently been identified as the key metabolite that is sensed to activate mTORC1 in glucose-replete conditions [134]. Downstream effectors of mTORC1 are kinases activating mRNA translation, importantly p70S6 kinase 1 (S6K1) and eIF4E binding protein (4EBP). Moreover, mTORC1 activates lipid biosynthesis by activating SREBP and promotes glycolysis by activating the translation of HIF-1 [133]. Active mTORC1 disrupts the interaction of AMPK and ULK1 thereby inhibiting autophagy [130]. Thus, the relative activity of mTORC1 and AMPK largely determines the extent of autophagy induction [133]. Nutrient availability is an important determinant of mTORC1 activity, however, growth-factor induced signaling pathways also play an important role. They converge on a key negative ON123300 regulator of mTORC1 signaling, the tuberous sclerosis complex (TSC) [133]. In contrast to the well-known environment-dependent activation of mTORC1, mTORC2 is activated by G-protein coupled receptors via the small GTPase KRas4b [135]. mTORC2 promotes the activation of AKT and thus modulates metabolism and migration [133]. Both mTOR complexes play an important role in cancer growth [136]. Inhibitors of mTORC1 have been approved for the treatment of advanced renal cell carcinoma and other cancers, yet response rates have been rather low in some studies [136]. Studies with mTORC1 inhibitors involving biomarker-based patient selection and or combinations with other drugs are on the way [136]. Despite the large body of knowledge on the mechanisms of mTORC1 activation in cancer cells, little is known about the regulatory function of mTORC1 to mediate metabolic plasticity. In fact, tumorigenic mutations and the phenotypic program activated by these mutations (e.g., proliferation, invasion) may render cancer cells specifically dependent on certain metabolic pathways, thereby limiting their flexibility. Accordingly, hyperactivation of mTORC1 by growth factor pathways has been shown ON123300 to increase the sensitivity towards glycolysis inhibitor 2-deoxyglucose [137]. 13. Targeting Metabolic Flexibility as Anticancer Strategy Antimetabolites targeting nucleoside biosynthetic pathways have been in clinical Rabbit polyclonal to K RAS use for cancer chemotherapy for almost 70 years [138]. The understanding of the enzymes and pathways involved led to continuous improvement of antimetabolite agents and therapeutic regimes. The development of agents targeting other central metabolic liabilities in cancer, like glycolysis or glutamine addiction, however, is still in its infancy. To selectively block biomass and/or energy production in cancer cells, thereby promoting cell death, is one of the main goals of antimetabolic therapies (Figure 4). The enhanced activation of metabolic activities, an important hallmark of cancer cells, may be the basis for a selective antitumorigenic effect of such treatments, sparing normal tissues. As outlined above, metabolic flexibility allows the continued synthesis of crucial biosynthetic precursors, like glycolytic or TCA cycle intermediates from alternative sources when the prime precursors are missing. Thus, metabolic flexibility may limit the efficacy of antimetabolic therapies. Certain treatments targeting metabolism that are effective in vitro might be ineffective in vivo due to the utilization of different sets of nutrients [25]. The simultaneous inhibition of different key metabolic pathways activated in cancer cells in an individual tumor might be of advantage in order to account for the flexible switching between different metabolic phenotypes. A model depicting such an approach is shown in Figure 4. In line with such a concept, simultaneous inhibition of respiratory complex I and glycolysis inhibited melanoma.