Principal Investigator

Mei
Kong
Awardee Organization

University Of California-Irvine
United States

Fiscal Year
2024
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Using dietary glutamine supplementation for melanoma prevention and targeted therapy

Despite recent advances in cancer metabolism, whether and how nutritional interventions affect tumor development, metastasis and therapeutic response are still poorly understood. Thus, the goal of this study is to elucidate the effect of glutamine supplementation on tumor development and therapeutic responses, and eventually provide molecular evidence that nutritional interventions on cancer patients can inhibit tumor growth and sensitize tumors to treatments. Using metabolomic analysis, we and others have found that, compared to other amino acids, many solid tumor cells are situated in a glutamine poor environment in vivo. Interestingly, we found that glutamine deficiency in melanoma tumors resulted in cancer cell de-differentiation and resistance to treatment due to increased histone methylation levels. This finding further prompted us to test if increases in glutamine levels through dietary supplementation can be detrimental to tumor cells that have been well adapted to a low glutamine environment. Our preliminary data demonstrated that supplementation of glutamine in the diet is sufficient to increase tumoral α-ketoglutarate levels and leads to decreased histone methylation in melanoma patient-derived xenograft (PDX) tumors. Importantly, we found that high glutamine diet significantly hinders tumor growth and decreases expression of melanoma-associated oncogenes compared to control diet. In support with this, accumulating evidence from in vivo experiments demonstrate that glutamine is not an essential nutritional source to support TCA cycle and tumor growth. Thus, we hypothesize that dietary glutamine supplementation inhibits melanoma tumor growth and sensitizes tumor cells to current treatments via epigenetic reprogramming. In this proposal, we will 1) determine the effect of dietary glutamine supplementation on melanoma tumor growth, metabolism and oncogene expression in vivo; 2) determine the molecular mechanisms by which glutamine supplementation inhibits tumor growth; 3) investigate the effect of glutamine supplementation in response to BRAF/MEK inhibitors and immunotherapy for melanoma treatment. Despite many proven clinical benefits of glutamine supplementation to cancer patients, recent in vitro studies showing that tumor cells are avid glutamine consumers led to cautionary usage of dietary glutamine on cancer patients. Completion of the proposed studies will provide insight into glutamine driven epigenetic regulation and its effect on tumor growth. The results of these studies will reveal a novel therapeutic direction for using dietary glutamine supplementation to prevent tumor growth and enhance therapeutic responses without detrimental side effects.

Publications

  • Yang Y, Reid MA, Hanse EA, Li H, Li Y, Ruiz BI, Fan Q, Kong M. SAPS3 subunit of protein phosphatase 6 is an AMPK inhibitor and controls metabolic homeostasis upon dietary challenge in male mice. Nature communications. 2023 Mar 13;14(1):1368. PMID: 36914647
  • Ruiz BI, Lowman XH, Yang Y, Fan Q, Wang T, Wu H, Hanse EA, Kong M. Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia. Genes. 2023 Sep 19;14. (9). PMID: 37761958
  • Naciri I, Andrade-Ludena MD, Yang Y, Kong M, Sun S. An emerging link between lncRNAs and cancer sex dimorphism. Human genetics. 2023 Dec 14. Epub 2023 Dec 14. PMID: 38095719
  • Hanse EA, Kong M. A happy cell stays home: When metabolic stress creates epigenetic advantages in the tumor microenvironment. Frontiers in oncology. 2022 Aug 26;12:962928. doi: 10.3389/fonc.2022.962928. eCollection 2022. PMID: 36091163
  • Franco CN, Seabrook LJ, Nguyen ST, Yang Y, Campos M, Fan Q, Cicchetto AC, Kong M, Christofk HR, Albrecht LV. Vitamin B6 is governed by the local compartmentalization of metabolic enzymes during growth. Science advances. 2023 Sep 8;9(36):eadi2232. Epub 2023 Sep 8. PMID: 37682999
  • Hanse EA, Wang T, Tifrea D, Senthil M, Kim AC, Kong M, Eng OS. A Novel Assessment of Metabolic Pathways in Peritoneal Metastases from Low-Grade Appendiceal Mucinous Neoplasms. Annals of surgical oncology. 2023 Aug;30(8):5132-5141. Epub 2023 May 6. PMID: 37149550