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FOXO3a-regulated arginine metabolic plasticity adaptively promotes esophageal cancer proliferation and metastasis

Oncogene volume 43, pages 216–223 (2024)Cite this article

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Abstract

Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor with a poor prognosis due to a lack of early detection. Indeed, the mechanisms underlying ESCC progression remain unclear. Here, we discovered that abnormal arginine metabolism contributes to ESCC progression. Based on transcriptomic and metabolomic analyses, we found that argininosuccinate synthetase 1 (ASS1) and argininosuccinate lyase (ASL) levels were increased in primary tumor tissues but decreased in lymph-metastatic tumor tissues. Intriguingly, FOXO3a was inversely correlated with ASS1 and ASL in primary and metastatic tumor tissues, suggesting that FOXO3a dissimilarly regulates ASS1 and ASL at different stages of ESCC. Silencing ASS1/ASL inhibited primary tumor growth and promoted metastasis. Conversely, overexpression of ASS1/ASL or increased arginine supply promoted tumor proliferation but suppressed metastasis. In addition, FOXO3a activation inhibited primary tumor growth by repressing ASS1 and ASL transcription, whereas inactivation of FOXO3a impeded metastasis by releasing ASS1 and ASL transcription. Together, the finding sheds light on metastatic reprogramming in ESCC.

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Fig. 1: ASS1 and ASL mRNA and metabolite profiles in primary and metastatic ESCC tissues.
Fig. 2: The effects of ASS1 and ASL on tumor proliferation and metastasis.
Fig. 3: FOXO3a-mediated transcriptional repression of ASS1 and ASL in ESCC cells.
Fig. 4: The effect of FOXO3a on tumor proliferation and metastasis.

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References

  1. di Pietro M, Canto MI, Fitzgerald RC. Endoscopic management of early adenocarcinoma and squamous cell carcinoma of the esophagus: screening, diagnosis, and therapy. Gastroenterology. 2018;154:421–36.

    Article  PubMed  Google Scholar 

  2. Ohashi S, Miyamoto S, Kikuchi O, Goto T, Amanuma Y, Muto M. Recent advances from basic and clinical studies of esophageal squamous cell carcinoma. Gastroenterology. 2015;149:1700–15.

    Article  PubMed  Google Scholar 

  3. Zhang W, Hong R, Li L, Wang Y, Du P, Ou Y, et al. The chromosome 11q13.3 amplification associated lymph node metastasis is driven by miR-548k through modulating tumor microenvironment. Mol Cancer. 2018;17:125S.

    Article  Google Scholar 

  4. Abnet CC, Arnold M, Wei WQ. Epidemiology of esophageal squamous cell carcinoma. Gastroenterology. 2018;154:360–73.

    Article  PubMed  Google Scholar 

  5. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  6. Morris SM Jr. Arginine: beyond protein. Am J Clin Nutr. 2006;83:508S–512S.

    Article  CAS  PubMed  Google Scholar 

  7. Patil MD, Bhaumik J, Babykutty S, Banerjee UC, Fukumura D. Arginine dependence of tumor cells: targeting a chink in cancer’s armor. Oncogene. 2016;35:4957–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hall PE, Lewis R, Syed N, Shaffer R, Evanson J, Ellis S, et al. A phase I study of pegylated arginine deiminase (pegargiminase), csplatin, and pemetrexed in argininosuccinate synthetase 1-deficient recurrent high-grade glioma. Clin Cancer Res. 2019;25:2708–16.

    Article  CAS  PubMed  Google Scholar 

  9. Szlosarek PW, Steele JP, Nolan L, Gilligan D, Taylor P, Spicer J, et al. Arginine deprivation with pegylated arginine deiminase in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma: a randomized clinical trial. JAMA Oncol. 2017;3:58–66.

    Article  PubMed  Google Scholar 

  10. Cai J, Fang L, Hang Y, Li R, Yuan J, Yang Y, et al. miR-205 targets PTEN and PHLPP2 to augment AKT signaling and drive malignant phenotypes in non-small cell lung cancer. Cancer Res. 2013;73:5402–15.

    Article  CAS  PubMed  Google Scholar 

  11. Cai J, Li R, Xu X, Zhang L, Lian R, Fang L, et al. CK1α suppresses lung tumour growth by stabilizing PTEN and inducing autophagy. Nat Cell Biol. 2018;20:465–78.

    Article  CAS  PubMed  Google Scholar 

  12. Luo H, Yang Y, Duan J, Wu P, Jiang Q, Xu C. PTEN-regulated AKT/FoxO3a/Bim signaling contributes to reactive oxygen species-mediated apoptosis in selenite-treated colorectal cancer cells. Cell Death Dis. 2013;4:e481.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lemos H, Huang L, Prendergast GC, Mellor AL. Immune control by amino acid catabolism during tumorigenesis and therapy. Nat Rev Cancer. 2019;19:162–75.

    Article  CAS  PubMed  Google Scholar 

  14. Bean GR, Kremer JC, Prudner BC, Schenone AD, Yao JC, Schultze MB, et al. A metabolic synthetic lethal strategy with arginine deprivation and chloroquine leads to cell death in ASS1-deficient sarcomas. Cell Death Dis. 2016;7:e2406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gaude E, Frezza C. Tissue-specific and convergent metabolic transformation of cancer correlates with metastatic potential and patient survival. Nat Commun. 2016;7:13041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ouimet M, Koster S, Sakowski E, Ramkhelawon B, van Solingen C, Oldebeken S, et al. Mycobacterium tuberculosis induces the miR-33 locus to reprogram autophagy and host lipid metabolism. Nat Immunol. 2016;17:677–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ, et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature. 2002;419:316–21.

    Article  CAS  PubMed  Google Scholar 

  18. Chu Z, Huo N, Zhu X, Liu H, Cong R, Ma L, et al. FOXO3A-induced LINC00926 suppresses breast tumor growth and metastasis through inhibition of PGK1-mediated Warburg effect. Mol Ther. 2021;9:2737–53.

    Article  Google Scholar 

  19. Chang X, Liu X, Wang H, Yang X, Gu Y. Glycolysis in the progression of pancreatic cancer. Am J Cancer Res. 2022;12:861–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhang X, Liu Q, Zhang X, Guo K, Zhang X, Zhou Z. FOXO3a regulates lipid accumulation and adipocyte inflammation in adipocytes through autophagy: role of FOXO3a in obesity. Inflamm Res. 2021;70:591–603.

    Article  CAS  PubMed  Google Scholar 

  21. Chen H, Wang SH, Chen C, Yu XY, Zhu JN, Mansell T, et al. A novel role of FoxO3a in the migration and invasion of trophoblast cells: from metabolic remodeling to transcriptional reprogramming. Mol Med. 2022;28:92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liu Y, Ao X, Ding W, Ponnusamy M, Wu W, Hao X, et al. Critical role of FOXO3a in carcinogenesis. Mol Cancer. 2018;17:104.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Stan SD, Hahm ER, Warin R, Singh SV. Withaferin A causes FOXO3a- and Bim-dependent apoptosis and inhibits growth of human breast cancer cells in vivo. Cancer Res. 2008;68:7661–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fitzwalter BE, Towers CG, Sullivan KD, Andrysik Z, Hoh M, Ludwig M, et al. Autophagy inhibition mediates apoptosis sensitization in cancer therapy by relieving FOXO3a turnover. Dev Cell. 2018;44:555–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang W, Zhang S, Yan P, Ren J, Song M, Li J, et al. A single-cell transcriptomic landscape of primate arterial aging. Nat Commun. 2020;11:2202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sundaresan NR, Gupta M, Kim G, Rajamohan SB, Isbatan A, Gupta MP. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice. J Clin Invest. 2009;119:2758–71.

    CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by the Jiangsu Provincial Key Research Development Program (BE 2017759) to QZ, the National Natural Science Foundation of China Research Grants (81972742, 81572742, 81372199) and the National Program on Key Research Project of China (No. 2016YFC0905900) to YX.

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Author notes

  1. These authors contributed equally: Wenbo Sun, Hengyuan Kou.

Authors and Affiliations

  1. Affiliated Eye Hospital, Nanjing Medical University, 138 Hanzhong Road, Nanjing, 210029, China

    Wenbo Sun, Hengyuan Kou, Yao Fang, Fan Xu, Zhi Xu, Qin Jiang & Yong Xu

  2. Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China

    Wenbo Sun, Fan Xu, Rong Yin, Qin Zhang & Yong Xu

  3. Department of Thoracic Surgery, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, China

    Wenbo Sun

  4. Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Nanjing Medical University, 101 Longman Avenue, Nanjing, 211166, China

    Hengyuan Kou, Yao Fang, Zhi Xu, Xiumei Wang & Yong Xu

Authors
  1. Wenbo Sun
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Contributions

WS contributed to the methodology development, omics analysis, investigation, data curation, formal analysis, and writing draft. HK contributed to methodology, investigation, data curation, formal analysis, and validation. contributed to, and omics analysis. YF, FX, ZX, and XW contributed to methodology, collection of patient samples data curation and formal analysis. RY contributed to the resources and project support. QZ contributed to the resources, supervision and funding acquisition. QJ contributed to resources, technical and facility support, and administration. YX contributed to project conception and design, investigation, data interpretation, supervision, funding acquisition, and manuscript writing, review and editing.

Corresponding authors

Correspondence to Qin Zhang, Qin Jiang or Yong Xu.

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Sun, W., Kou, H., Fang, Y. et al. FOXO3a-regulated arginine metabolic plasticity adaptively promotes esophageal cancer proliferation and metastasis. Oncogene 43, 216–223 (2024). https://doi.org/10.1038/s41388-023-02906-0

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