Abstract 3745: Exogenous and endogenous sources of serine contribute to colon cancer metabolism and growth

Abstract

Serine is a non-essential amino acid that is generated by the sequential actions of phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT1) and phosphoserine phosphatase (PSPH). Increased serine biosynthesis occurs in several cancers and supports tumor growth. In addition to serine synthesis, exogenous serine is taken up by cells and can also fuel tumor growth. Interestingly, colon cancer cells increase expression of serine biosynthesis enzymes in the absence of exogenous serine, suggesting a compensatory adaptive response to reduced availability of serine. This study explored the relative contributions of exogenous and synthesized serine to colon cancer cell growth, metabolism and response to anti-cancer therapy. We found that PSAT1 expression was markedly increased in human colonic adenomas and colorectal cancer (CRC) compared to normal adjacent tissue. Additionally, high levels of PSAT1 in CRC were associated with reduced patient survival. Deletion of PSAT1 only modestly reduced colon cancer cell proliferation in vitro. Removal of serine from the medium strongly suppressed cell proliferation whereas the combination of removing exogenous serine and deleting PSAT1 caused even greater inhibition of cell proliferation. Metabolite profiling revealed altered nucleotide levels upon exogenous serine depletion, an effect that was enhanced when PSAT1 was deleted. Global gene expression profiling showed approximately 3,000 differentially expressed genes when only exogenous serine was removed, with an additional ~800 changes in PSAT1 knockout (KO) cells grown in serine deficient medium. A marked DNA damage response was induced selectively in PSAT1KO cells in serine deficient medium, which was prevented by the addition of formate. Xenografts derived from PSAT1 sufficient and PSAT1KO cells showed that neither PSAT1 deletion alone nor removal of dietary serine alone affected tumor growth, but the combination resulted in profound growth suppression. Additionally, treatment with 5-fluorouracil (5-FU) in the xenograft model induced a strong regression of established tumors derived from mice carrying PSAT1KO cells fed a serine deficient diet. Complementary in vitro studies showed enhanced sensitivity of PSAT1KO cells grown in serine deficient medium to 5-FU induced death, which was preceded by specific metabolite changes including markedly reduced levels of TMP and TTP. Taken together, our results suggest that both exogenous and endogenous sources of serine are important contributors to colon cancer cell proliferation and metabolism. Limiting exogenously available and synthesized serine may be an effective strategy to limit colon cancer growth and enhance the efficacy of treatment. Citation Format: David C. Montrose, Miguel Foronda, Suchandrima Saha, Erin M. McNally, Xi Kathy Zhou, Jan Krumsiek, Akanksha Verma, Olivier Elemento, Rhonda K. Yantiss, Qiuying Chen, Steven S. Gross, Lorenzo Galluzzi, Lukas E. Dow, Andrew J. Dannenberg. Exogenous and endogenous sources of serine contribute to colon cancer metabolism and growth [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3745.

Linking Serine/Glycine Metabolism to Radiotherapy Resistance

“…5-FU resistance has been linked to PSAT1 overexpression since combined CRISPR-based deletion of PSAT1 and serine withdrawal suppressed CRC xenograft tumor growth and enhanced the sensitivity to 5-FU by increasing DNA damage and diminishing the nucleotide pool, resulting in cell death. Thus, this study suggests that both endogenous and exogenous serine contributes to CRC growth and resistance to 5-FU [ 77 ].…”

“…The therapeutic strategies targeting serine/glycine metabolism include limiting the availability of exogenous serine and glycine in serine uptake-dependent cancers by diet restriction and targeting the enzymes of de novo serine/glycine biosynthesis pathway [ 16 , 77 , 155 ]. Therefore, it is essential to determine which cancer patients would benefit from these strategies.…”