Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/144809
Title: Targeted inhibition of purine metabolism is effective in suppressing hepatocellular carcinoma progression
Authors: Chong, Yong Chun
Toh, Tan Boon
Chan, Zhiling
Lin, Quy Xiao Xuan
Thng, Dexter Kai Hao
Hooi, Lissa
Ding, Zhaobing
Shuen, Timothy
Toh, Han Chong
Dan, Yock Young
Bonney, Glenn Kunnath
Zhou, Lei
Chow, Pierce
Wang, Yulan
Benoukraf, Touati
Chow, Edward Kai-Hua
Han, Weiping
Keywords: Science::Medicine
Issue Date: 2020
Source: Chong, Y. C., Toh, T. B., Chan, Z., Lin, Q. X. X., Thng, D. K. H., Hooi, L., . . . Han, W. (2020). Targeted Inhibition of Purine Metabolism Is Effective in Suppressing Hepatocellular Carcinoma Progression. Hepatology Communications, 4(9), 1362–1381. doi:10.1002/hep4.1559
Journal: Hepatology communications
Abstract: Tumor-specific metabolic rewiring, acquired to confer a proliferative and survival advantage over nontransformed cells, represents a renewed focus in cancer therapy development. Hepatocellular carcinoma (HCC), a malignancy that has hitherto been resistant to compounds targeting oncogenic signaling pathways, represents a candidate cancer to investigate the efficacy of selectively antagonizing such adaptive metabolic reprogramming. To this end, we sought to characterize metabolic changes in HCC necessary for tumorigenesis. We analyzed gene expression profiles in three independent large-scale patient cohorts who had HCC. We identified a commonly deregulated purine metabolic signature in tumors with the extent of purine biosynthetic enzyme up-regulation correlated with tumor grade and a predictor of clinical outcome. The functional significance of enhanced purine metabolism as a hallmark in human HCC was then validated using a combination of HCC cell lines, patient-derived xenograft (PDX) organoids, and mouse models. Targeted ablation of purine biosynthesis by knockdown of the rate-limiting enzyme inosine-5'-monophosphate dehydrogenase (IMPDH) or using the drug mycophenolate mofetil (MMF) reduced HCC proliferation in vitro and decreased the tumor burden in vivo. In comparing the sensitivities of PDX tumor organoids to MMF therapy, we found that HCC tumors defined by high levels of IMPDH and guanosine nucleosides were most susceptible to treatment. Mechanistically, a phosphoinositide 3-kinase (PI3K)-E2F transcription factor 1 (E2F1) axis coordinated purine biosynthetic enzyme expression, deregulation of which altered the activity of mitogen-activated protein kinase/RAS signaling. Simultaneously abolishing PI3K signaling and IMPDH activity with clinically approved inhibitors resulted in greatest efficacy in reducing tumor growth in a PDX mouse model. Conclusion: Enhanced purine metabolic activity regulated by PI3K pathway-dependent activation of E2F1 promotes HCC carcinogenesis, suggesting the potential for targeting purine metabolic reprogramming as a precision therapeutic strategy for patients with HCC.
URI: https://hdl.handle.net/10356/144809
ISSN: 2471-254X
DOI: 10.1002/hep4.1559
Rights: © 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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