Liver cancer growth tied to tryptophan intake
Diet free of this essential amino acid stops liver cancer in preclinical models by targeting a key metabolite, UT Southwestern researchers report
DALLAS – July 31, 2024 – Researchers at UT Southwestern Medical Center have discovered that a diet free of the amino acid tryptophan can effectively halt the growth of liver cancer in mice. Their findings, published in Nature Communications, offer new insights for dietary-based cancer treatments and highlight the critical role of the tryptophan metabolite indole 3-pyruvate (I3P) in liver tumor development.
“This work demonstrates that tailored dietary modulation may serve as a powerful adjuvant in cancer treatment,” said study leader Maralice Conacci-Sorrell, Ph.D., Associate Professor of Cell Biology and Children’s Medical Center Research Institute at UT Southwestern (CRI) and a member of the Cellular Networks in Cancer Research Program of the Harold C. Simmons Comprehensive Cancer Center. “It builds on our lab’s discovery that the universal oncogene MYC increases the demand for tryptophan in liver tumors.”
Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related mortality worldwide, according to 2020 data from the World Health Organization, with limited options for effective treatment and a five-year survival rate of about 30%. The study shows that growth of liver cancers driven by the MYC oncogene is particularly dependent on tryptophan, which is converted into I3P as well as other metabolites.
By removing tryptophan from the diet of mice, researchers stopped the growth of MYC-driven liver tumors and restored normal gene expression in liver cells. Notably, this dietary intervention did not affect protein synthesis in normal cells, suggesting a targeted therapeutic approach that spares healthy tissues.
“Liver tumors require large amounts of tryptophan to generate the oncometabolite I3P,” Dr. Conacci-Sorrell said. “A tryptophan-free diet prevents liver tumor growth by a mechanism that depends on I3P but is independent of translation, the process by which proteins are synthesized from amino acid building blocks. Because tryptophan is the amino acid with the lowest abundance in the proteome, short-term dietary manipulation is safe for healthy tissues but not for cancer cells.”
Among foods high in tryptophan are turkey, red meat, pork, chicken, tofu, milk, soybeans (including edamame), quinoa, oats, and fish.
The research highlights the complex role of tryptophan metabolism in cancer. While tryptophan is known to be metabolized into several important compounds, including the neurotransmitter serotonin and kynurenine, a precursor of the B vitamin niacin, the study showed that MYC-driven liver tumors preferentially utilize tryptophan to produce I3P rather than kynurenine. This shift underscores the potential for targeting specific metabolic pathways in cancer treatment.
The researchers also found that supplementation with I3P restored the growth of tryptophan-starved liver cancer cells, further emphasizing the critical role of this metabolite in cancer development. These findings suggest that targeting I3P or its production pathway could be a viable therapeutic strategy.
“This study not only advances understanding of liver cancer biology but also suggests a promising approach for developing personalized cancer therapies,” Dr. Conacci-Sorrell said.
The study’s co-first authors are Niranjan Venkateswaran, M.S., former research associate; Roy Garcia, B.S., graduate student researcher; Maria del Carmen Lafita Navarro, Ph.D., and Yi-Heng Hao, Ph.D., both Instructors of Cell Biology; and Lizbeth Perez-Castro, Ph.D., and Pedro A. S. Nogueira, Ph.D., both postdoctoral fellows in the Sorrell Lab.
Other UTSW researchers who contributed to this study are Ashley Solmonson, Ph.D., Assistant Professor in the Cecil H. and Ida Green Center for Reproductive Biology Sciences and of Obstetrics and Gynecology; Andrew Lemoff, Ph.D., Assistant Professor of Biochemistry; Nick V. Grishin, Ph.D., Professor of Biophysics and Biochemistry; Lin Xu, Ph.D., Assistant Professor in the Peter O’Donnell Jr. School of Public Health and of Pediatrics; Noelle S. Williams, Ph.D., Professor of Biochemistry; Jerry W. Shay, Ph.D., Professor of Cell Biology and a Distinguished Teaching Professor; Ralph J. DeBerardinis, M.D., Ph.D., Professor in CRI and the Eugene McDermott Center for Human Growth and Development and of Pediatrics; Hao Zhu, M.D., Professor in CRI and of Internal Medicine and Pediatrics; Jessica A. Kilgore, B.S., Research Scientist; Shun Fang, M.D., Ph.D., postdoctoral fellow in the Sorrell Lab; Isabella N. Brown, B.S., graduate student researcher; Li Li, M.D., Senior Research Scientist; Emily Parks, B.S., graduate and medical student researcher; Igor Lopes dos Santos, M.S., graduate student researcher; Mahima Bhaskar, Green Fellow and Laboratory Technician; Jiwoong Kim, M.S., Computational Biologist; and Lisa Kinch, Ph.D., bioinformatics specialist in the Orth Lab.
Dr. Conacci-Sorrell holds the John P. Perkins, Ph.D. Distinguished Professorship in Biomedical Science. Dr. DeBerardinis holds the Joel B. Steinberg, M.D. Distinguished Chair in Pediatrics and is co-leader of the Cellular Networks in Cancer Research Program of the Simmons Cancer Center, an Investigator of the Howard Hughes Medical Institute, and a Sowell Family Scholar in Medical Research. Dr. Grishin holds the Cecil H. and Ida M. Green Chair in Biomedical Science. Dr. Shay holds The Southland Financial Corporation Distinguished Chair in Geriatrics. Dr. Zhu is co-leader of the Development and Cancer Research Program in the Simmons Cancer Center and holds the Nancy B. and Jake L. Hamon Distinguished Chair in Therapeutic Oncology Research.
Drs. Conacci-Sorrell and Grishin are Virginia Murchison Linthicum Scholars in Medical Research. Drs. Shay, Williams, and Xu are also members of Simmons Cancer Center.
This study was funded by the American Cancer Society (724003), the Cancer Prevention and Research Institute of Texas (RP220046, RP210041), National Cancer Institute (NCI) (R35CA22044901, R01CA245548, R01 CA251928), The Welch Foundation (I-2058-20210327), National Institute of General Medical Sciences (GM145744-01), a Circle of Friends Award, Simmons Comprehensive Cancer Center Cancer & Obesity Translational Pilot Award, Mark Foundation (21-003-ELA), National Science Foundation (2022344499), a Mary Kay postdoctoral fellowship, the HHMI Gilliam Fellows Program, and a NCI Cancer Center Support Grant (P30CA142543).
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.