Journal of Kerman University of Medical Sciences

Altered expression of genes involved in the serine synthesis pathway (SSP) in patients with acute myeloid leukemia

Document Type : Original Article

Authors

Parinaz Khadem 1
Ali Keshavarz 1
Mohammad Hossein Mohammadi 1, 2
Fateme Mezginejad 3
Mehdi Allahbakhshian Farsani 1

1 Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

2 Hematopoietic Stem Cell Transplantation (HSCT) Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

3 Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran

https://doi.org/10.34172/jkmu.3660
Abstract
 Background: Acute myeloid leukemia (AML) is characterized by the uncontrolled proliferation of malignant cells, which rely on various metabolic pathways to sustain their survival and growth. In this regard, the serine synthesis pathway (SSP) is critically involved in generating biological macromolecules and oncogenic metabolites that are fundamental in tumor growth and proliferation. As a result, this study aimed to assess the expression of SSP-related genes, including Phosphoserine aminotransferase (PSAT1), phosphoglycerate dehydrogenase (PHGDH), and 1-3-phosphoserine phosphatase (PSPH) in AML patients.
Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess the expression of PHGDH, PSAT1, and PSPH genes in samples from 60 newly diagnosed AML patients and 10 healthy controls.
Results: Our investigation revealed decreased expression of PSAT1 and PSPH in AML patients compared to controls (P = 0.002, P = 0.026, respectively). However, no significant change was observed in PHGDH expression. Moreover, positive correlations were identified between the expression levels of PHGDH and PSAT1 (r = 0.488, P = 0.0002), PHGDH and PSPH (r = 0.379, P = 0.007), and PSAT1 and PSPH (r = 0.331, P = 0.01) in AML patients.
Conclusion: Although malignant cells are exposed to serine restriction, it seems that SSP up-regulation is not beneficial to myeloid blasts. This may be justified by applying alternative sources to compensate required serine for these cells. More investigations can shed light on the importance of alternative sources as therapeutic targets in AML patients.

Highlights

Mehdi Allahbakhshian Farsani (Google Scholar) (PubMed)

Keywords

Serine biosynthesis
Phosphoglycerate dehydrogenase
Phosphoserine aminotransferase
Phosphoserine phosphatase
Subjects
  1. Salarpour F, Goudarzipour K, Mohammadi MH, Ahmadzadeh A, Faraahi S, Allahbakhshian Farsani M. Evaluation of CCAAT/ enhancer binding protein (C/EBP) Alpha (CEBPA) and runt-related transcription factor 1 (RUNX1) expression in patients with de novo acute myeloid leukemia. Ann Hum Genet. 2017;81(6):276-83. doi: 10.1111/ahg.12210.
  2. Mizani S, Keshavarz A, Vazifeh Shiran N, Bashash D, Allahbakhshian Farsani M. Expression changes of SIRT1 and FOXO3a significantly correlate with oxidative stress resistance genes in AML patients. Indian J Hematol Blood Transfus. 2023;39(3):392-401. doi: 10.1007/s12288-022-01612-3.
  3. Kargar-Sichani Y, Mohammadi MH, Amiri V, Barzegar M, Keshavarz A, Bashash D, et al. Effect of acute myeloid leukemia-derived extracellular vesicles on bone marrow mesenchymal stromal cells: expression of poor prognosis genes. Arch Med Res. 2023;54(2):95-104. doi: 10.1016/j. arcmed.2022.12.008.
  4. Eriksson A, Lennartsson A, Lehmann S. Epigenetic aberrations in acute myeloid leukemia: early key events during leukemogenesis. Exp Hematol. 2015;43(8):609-24. doi: 10.1016/j.exphem.2015.05.009.
  5. Kottakis F, Nicolay BN, Roumane A, Karnik R, Gu H, Nagle JM, et al. LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature. 2016;539(7629):390- 5. doi: 10.1038/nature20132.
  6. Amelio I, Cutruzzolá F, Antonov A, Agostini M, Melino G. Serine and glycine metabolism in cancer. Trends Biochem Sci. 2014;39(4):191-8. doi: 10.1016/j.tibs.2014.02.004.
  7. Yang M, Vousden KH. Serine and one-carbon metabolism in cancer. Nat Rev Cancer. 2016;16(10):650-62. doi: 10.1038/ nrc.2016.81.
  8. Polet F, Corbet C, Pinto A, Rubio LI, Martherus R, Bol V, et al. Reducing the serine availability complements the inhibition of the glutamine metabolism to block leukemia cell growth. Oncotarget. 2016;7(2):1765-76. doi: 10.18632/ oncotarget.6426.
  9. Yang Y, Wu J, Cai J, He Z, Yuan J, Zhu X, et al. PSAT1 regulates cyclin D1 degradation and sustains proliferation of non-small cell lung cancer cells. Int J Cancer. 2015;136(4):E39-50. doi: 10.1002/ijc.29150.
  10. Regan JD, Vodopick N, Takeda S, Lee WH, Faulcon FM. Serine requirement in leukemic and normal blood Science. 1969;163(3874):1452-3. doi: 10.1126/ science.163.3874.1452.
  11. Tedeschi PM, Markert EK, Gounder M, Lin H, Dvorzhinski D, Dolfi SC, et al. Contribution of serine, folate and glycine metabolism to the ATP, NADPH and purine requirements of cancer cells. Cell Death Dis. 2013;4(10):e877. doi: 10.1038/ cddis.2013.393.
  12. Muñoz-Pinedo C, El Mjiyad N, Ricci JE. Cancer metabolism: current perspectives and future directions. Cell Death Dis. 2012;3(1):e248. doi: 10.1038/cddis.2011.123.
  13. Levenson VV. DNA methylation as a universal biomarker. Expert Rev Mol Diagn. 2010;10(4):481-8. doi: 10.1586/ erm.10.17.
  14. Spencer DH, Russler-Germain DA, Ketkar S, Helton NM, Lamprecht TL, Fulton RS, et al. CpG island hypermethylation mediated by DNMT3A is a consequence of AML progression. Cell. 2017;168(5):801-16.e13. doi: 10.1016/j. cell.2017.01.021.
  15. Hart CE, Race V, Achouri Y, Wiame E, Sharrard M, Olpin SE, et al. Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway. Am J Hum Genet. 2007;80(5):931-7. doi: 10.1086/517888.
  16. Bjelosevic S, Gruber E, Newbold A, Shembrey C, Devlin JR, Hogg SJ, et al. Serine biosynthesis is a metabolic vulnerability in FLT3-ITD-driven acute myeloid leukemia. Cancer Discov. 2021;11(6):1582-99. doi: 10.1158/2159-8290.Cd-20-0738.
  17. Bachelor MA, Lu Y, Owens DM. L-3-phosphoserine phosphatase (PSPH) regulates cutaneous squamous cell carcinoma proliferation independent of L-serine biosynthesis. J Dermatol Sci. 2011;63(3):164-72. doi: 10.1016/j. jdermsci.2011.06.001.
  18. Fan J, Teng X, Liu L, Mattaini KR, Looper RE, Vander Heiden MG, et al. Human phosphoglycerate dehydrogenase produces the oncometabolite D-2-hydroxyglutarate. ACS Chem Biol. 2015;10(2):510-6. doi: 10.1021/cb500683c.
  19. Jing Z, Heng W, Xia L, Ning W, Yafei Q, Yao Z, et al. Downregulation of phosphoglycerate dehydrogenase inhibits proliferation and enhances cisplatin sensitivity in cervical adenocarcinoma cells by regulating Bcl-2 and caspase-3. Cancer Biol Ther. 2015;16(4):541-8. doi: 10.1080/15384047.2015.1017690.
  20. Song Z, Feng C, Lu Y, Lin Y, Dong C. PHGDH is an independent prognosis marker and contributes cell proliferation, migration and invasion in human pancreatic cancer. Gene. 2018;642:43- 50. doi: 10.1016/j.gene.2017.11.014.
  21. Jia XQ, Zhang S, Zhu HJ, Wang W, Zhu JH, Wang XD, et al. Increased expression of PHGDH and prognostic significance in colorectal cancer. Transl Oncol. 2016;9(3):191-6. doi: 10.1016/j.tranon.2016.03.006.
  22. Liu J, Guo S, Li Q, Yang L, Xia Z, Zhang L, et al. Phosphoglycerate dehydrogenase induces glioma cells proliferation and invasion by stabilizing forkhead box M1. J Neurooncol. 2013;111(3):245-55. doi: 10.1007/s11060-012- 1018-x.
  23. Vié N, Copois V, Bascoul-Mollevi C, Denis V, Bec N, Robert B, et al. Overexpression of phosphoserine aminotransferase PSAT1 stimulates cell growth and increases chemoresistance of colon cancer cells. Mol Cancer. 2008;7:14. doi: 10.1186/1476-4598-7-14.
  24. Kim SK, Jung WH, Koo JS. Differential expression of enzymes associated with serine/glycine metabolism in different breast cancer subtypes. PLoS One. 2014;9(6):e101004. doi: 10.1371/journal.pone.0101004.
  25. Iwamoto S, Mihara K, Imai C, Campana D. L-serine produced by mesenchymal cells in the bone marrow microenvironment is a trophic factor for hematopoietic progenitor cells. Blood. 2005;106(11):590. doi: 10.1182/blood.V106.11.590.590.
  26. Sponagel J, Devarakonda S, Rubin JB, Luo J, Ippolito JE. De novo serine biosynthesis from glucose predicts sex-specific response to antifolates in non-small cell lung cancer cell lines. iScience. 2022;25(11):105339. doi: 10.1016/j. isci.2022.105339.
Journal of Kerman University of Medical Sciences
Volume 32
Pages 1-7

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