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Review
. 2015;11(8):1198-208.
doi: 10.1080/15548627.2015.1053680.

Glutaminolysis and autophagy in cancer

Victor H Villar  1 , Faten Merhi, Mojgan Djavaheri-Mergny, Raúl V Durán
Affiliations
Review

Glutaminolysis and autophagy in cancer

Victor H Villar et al. Autophagy. 2015.

Abstract

The remarkable metabolic differences between cancer cells and normal cells result in the potential for targeted cancer therapy. The upregulation of glutaminolysis provides energetic advantages to cancer cells. The recently described link between glutaminolysis and autophagy, mediated by MTORC1, may constitute an attractive target for therapeutic strategies. A combination of therapies targeting simultane-ously cell signaling, cancer metabolism, and autophagy can solve therapy resistance and tumor relapse problems, commonly observed in patients treated with most of the current targeted therapies. In this review we summarize the mechanistic link between glutaminolysis and autophagy, and discuss the impacts of these processes on cancer progression and the potential for therapeutic intervention.

Keywords: MTOR; ROS; autophagy; cancer; glutaminolysis; prolyl hydroxylases; α-ketoglutarate.

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Figures

Figure 1.
Figure 1.
Glutamine metabolism and metabolic transformation. In highly proliferating cells, citrate is diverted away from the TCA cycle for the synthesis of lipids. In the cytoplasm, citrate is converted to acetyl-CoA and oxaloacetate by the enzyme ACLY (ATP citrate lyase). While acetyl-CoA is used for the synthesis of lipids, oxaloacetate is converted to malate. Cytosolic malate is converted to pyruvate and NADPH by ME (malic enzyme). GLS (glutaminase) deamidates glutamine into glutamate. Thereafter, glutamate is further deaminated by the enzyme GLUD1 (glutamate dehydrogenase 1) to yield αKG, which replenishes the TCA cycle. In addition, glutaminolytic αKG can be exported into the cytosol through SLC25A11, the mitochondrial αKG/malate carrier protein, where this metabolite activates EGLNs, which in turn activate MTORC1 to promote cell growth and anabolism. Several inhibitors of glutaminolysis (DON, BPTES) have shown a capacity to reduce MTORC1 activation and cell growth in cancer cells.
Figure 2.
Figure 2.
Regulation of autophagy by glutaminolysis. The generation of αKG by glutaminolysis activates EGLNs, which in turn promote MTORC1 activation. MTORC1 inhibits both the phosphatidylinositol 3-kinase (PtdIns3K) complex and ULK complex to prevent the initiation and vesicle nucleation steps of autophagy. The production of GSH, NADPH, and αKG by glutaminolysis limits the production of ROS to counteract the induction of autophagy. The accumulation of ROS induces the oxidation of ATG4, thus preventing the delipidation of the autophagy marker MAP1LC3-II, and activates MAPK8, which results in the dissociation of the BECN1-BCL2 complex. Under hypoxia, HIF1 induction activates BNIP3, which binds to BCL2 to activate autophagy by disrupting the interaction between BECN1 and BCL2. Finally, the reactivation of MTORC1 by glutaminolysis is necessary for lysosome regeneration and autophagy termination. Green arrows indicate processes that result in autophagy activation; red arrows indicate processes that result in autophagy inhibition.
Figure 3.
Figure 3.
Regulation of autophagy by the MTORC1 signaling pathway in cancer cells. Glutamine is taken up by cells through the transporter SLC1A5. In addition, the antiporter SLC7A5 effluxes glutamine to introduce leucine inside of the cells. Leucine activates GLUD1 (glutamate dehydrogenase 1) allosterically, to promote the production of αKG and the activation of MTORC1 in a EGLN-dependent manner. MTORC1 integrates several inputs, most of them converging in the activation/repression of the TSC1-TSC2 complex, which inhibits RHEB and thus MTORC1. Glutaminolysis activates RRAG proteins, which promote the translocation of MTORC1 to the surface of the lysosome where MTORC1 interacts with its coactivator RHEB. Active MTORC1 induces the phosphorylation of both ULK1 and TEFB to inhibit autophagy. In addition, glutamate, a precursor of GSH (glutathione), along with αKG counteracts ROS levels to inhibit the activation of autophagy mediated by ATM, AMPK, and TSC upstream of MTORC1. Autophagy plays a dual role in cancer: while in early stages autophagy suppresses tumor progression by the removal of damaged cellular components, autophagy promotes the growth and survival of established tumors by providing nutrients and energy at later stages. Green arrows indicate processes that result in autophagy activation; red arrows indicate processes that result in autophagy inhibition.
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