Glutamine is an essential nutrient to support the survival and proliferation of cancer cells, and increased use of glutamine to fuel anabolic processes has been observed in a wide variety of tumors. However, as tumors grow, increased glutamine catabolism often depletes the local supply, leading tumor cells to face periods of glutamine deprivation. How tumor cells sense glutamine levels and survive these temporary periods of glutamine deprivation is unclear, but such survival is necessary for tumors to persist. Our goal is to define the molecular pathways that regulate cell survival under low glutamine conditions and evaluate the potential of simultaneously blocking both glutamine metabolism and the adaptive survival response as a novel therapeutic approach for cancer treatment. We have recently shown that glutamine deprivation leads to induction of the protein phosphatase 2A regulatory subunit B55?, thereby triggering the formation of an active PP2A complex consisting of catalytic C and scaffolding A subunits and the specifically-induced B55? subunit. This B55?- containing PP2A complex is required for tumor cell survival upon glutamine depletion. We further found that induction of B55? activates p53, an important sensor of metabolic stress. Our preliminary data suggest that B55? activates p53 through a mechanism that involves dephosphorylation of EDD, a previously unidentified substrate of B55? that is a known negative regulator of p53. In addition, we have preliminary data indicating that IKK, the master regulator of NF-kB transcription factors, is phosphorylated upon glutamine deprivation and required for B55? induction. We therefore hypothesize that B55? is induced by the IKK pathway to dephosphorylate EDD, thereby leading to p53 activation and cancer cell survival under low glutamine conditions. Thus, targeting both glutamine metabolism and the IKK B55?-EDD-p53 survival pathway could be an effective therapeutic approach to kill tumor cells. To test this hypothesis, we propose three specific aims: 1) Determine the role of IKK in B55?-mediated activation of p53 and cell survival upon glutamine deprivation; 2) Examine if B55? activates p53 upon glutamine deprivation by dephosphorylating EDD; 3) Determine the combined effect of IKK and glutamine metabolism inhibition on growth of tumors with different p53 status. The results of the proposed studies will define the molecular mechanisms and functional impact of the IKK B55?-p53 pathway in the metabolic adaptive response to glutamine deprivation. A wide variety of human cancer cell lines are sensitive to glutamine starvation, and reagents that impair cells' ability to use glutamine are currently being studied as novel cancer therapies. The proposed studies will provide deeper understanding of the survival pathway used by cancer cells when glutamine metabolism is blocked, and thus will reveal novel therapeutic directions for targeting both glutamine metabolism and the survival pathway in order to efficiently kill tumor cells.

Public Health Relevance

Glutamine is an essential nutrient for cancer cell survival and proliferation, yet the signaling pathways that sense glutamine levels remain unknown. Our goal is to define molecular pathways that regulate cell survival under low glutamine conditions and test the potential of simultaneously blocking both glutamine metabolism and the adaptive survival response as a novel therapeutic approach for cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA183989-06
Application #
9550919
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Willis, Kristine Amalee
Project Start
2018-05-01
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2021-04-30
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
Ishak Gabra, Mari B; Yang, Ying; Lowman, Xazmin H et al. (2018) IKK? activates p53 to promote cancer cell adaptation to glutamine deprivation. Oncogenesis 7:93
Tran, Thai Q; Ishak Gabra, Mari B; Lowman, Xazmin H et al. (2017) Glutamine deficiency induces DNA alkylation damage and sensitizes cancer cells to alkylating agents through inhibition of ALKBH enzymes. PLoS Biol 15:e2002810
Tran, T Q; Lowman, X H; Reid, M A et al. (2017) Tumor-associated mutant p53 promotes cancer cell survival upon glutamine deprivation through p21 induction. Oncogene 36:1991-2001
Gao, Xia; Reid, Michael A; Kong, Mei et al. (2017) Metabolic interactions with cancer epigenetics. Mol Aspects Med 54:50-57
Tran, Thai Q; Lowman, Xazmin H; Kong, Mei (2017) Molecular Pathways: Metabolic Control of Histone Methylation and Gene Expression in Cancer. Clin Cancer Res 23:4004-4009
Reid, Michael A; Lowman, Xazmin H; Pan, Min et al. (2016) IKK? promotes metabolic adaptation to glutamine deprivation via phosphorylation and inhibition of PFKFB3. Genes Dev 30:1837-51
Pan, Min; Reid, Michael A; Lowman, Xazmin H et al. (2016) Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat Cell Biol 18:1090-101
Rosales, Kimberly Romero; Reid, Michael A; Yang, Ying et al. (2015) TIPRL Inhibits Protein Phosphatase 4 Activity and Promotes H2AX Phosphorylation in the DNA Damage Response. PLoS One 10:e0145938
Fong, Miranda Y; Zhou, Weiying; Liu, Liang et al. (2015) Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol 17:183-94
Hernandez-Davies, Jenny E; Tran, Thai Q; Reid, Michael A et al. (2015) Vemurafenib resistance reprograms melanoma cells towards glutamine dependence. J Transl Med 13:210

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