Metabolic pathway analyses identify proline biosynthesis pathway as a promoter of liver tumorigenesis

• Published in: Journal of hepatology Vol. 72; no. 4; pp. 725 - 735
• Main Authors: Ding, Zhaobing, Ericksen, Russell E., Escande-Beillard, Nathalie, Lee, Qian Yi, Loh, Abigail, Denil, Simon, Steckel, Michael, Haegebarth, Andrea, Wai Ho, Timothy Shen, Chow, Pierce, Toh, Han Chong, Reversade, Bruno, Gruenewald, Sylvia, Han, Weiping
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2020; Elsevier Science Ltd
• Subjects: Aldehyde Dehydrogenase - deficiency; Aldehyde Dehydrogenase - genetics; Animals; cancer; Carboxylate reductase; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinoma, Hepatocellular - chemically induced; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell growth; Cell proliferation; Cell Proliferation - genetics; delta-1-Pyrroline-5-Carboxylate Reductase; Diethylnitrosamine; Diethylnitrosamine - adverse effects; drug discovery; enzyme; Enzymes; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; HaCaT Cells; HEK293 Cells; Hep G2 Cells; Hepatocellular carcinoma; Hepatoma; Humans; Immunotherapy; Liver cancer; Liver Neoplasms - chemically induced; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Neoplasms, Experimental - genetics; Liver Neoplasms, Experimental - metabolism; Liver Neoplasms, Experimental - pathology; Male; Metabolic pathways; Metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Mice, SCID; oncology; Proline; Proline - biosynthesis; Pyrroline Carboxylate Reductases - deficiency; Pyrroline Carboxylate Reductases - genetics; Pyrroline-5-carboxylate reductase; Rats; Signal Transduction - genetics; therapy; Transcriptome; Transfection; Tumor Burden - genetics; Tumor cell lines; Tumorigenesis; Xenograft Model Antitumor Assays; enzyme; drug discovery; therapy; cancer; metabolism; hepatocellular carcinoma; oncology
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2019.10.026

Under the regulation of various oncogenic pathways, cancer cells undergo adaptive metabolic programming to maintain specific metabolic states that support their uncontrolled proliferation. As it has been difficult to directly and effectively inhibit oncogenic signaling cascades with pharmaceutical compounds, focusing on the downstream metabolic pathways that enable indefinite growth may provide therapeutic opportunities. Thus, we sought to characterize metabolic changes in hepatocellular carcinoma (HCC) development and identify metabolic targets required for tumorigenesis. We compared gene expression profiles of Morris Hepatoma (MH3924a) and DEN (diethylnitrosamine)-induced HCC models to those of liver tissues from normal and rapidly regenerating liver models, and performed gain- and loss-of-function studies of the identified gene targets for their roles in cancer cell proliferation in vitro and in vivo. The proline biosynthetic enzyme PYCR1 (pyrroline-5-carboxylate reductase 1) was identified as one of the most upregulated genes in the HCC models. Knockdown of PYCR1 potently reduced cell proliferation of multiple HCC cell lines in vitro and tumor growth in vivo. Conversely, overexpression of PYCR1 enhanced the proliferation of the HCC cell lines. Importantly, PYCR1 expression was not elevated in the regenerating liver, and KD or overexpression of PYCR1 had no effect on proliferation of non-cancerous cells. Besides PYCR1, we found that additional proline biosynthetic enzymes, such as ALDH18A1, were upregulated in HCC models and also regulated HCC cell proliferation. Clinical data demonstrated that PYCR1 expression was increased in HCC, correlated with tumor grade, and was an independent predictor of clinical outcome. Enhanced expression of proline biosynthetic enzymes promotes HCC cell proliferation. Inhibition of PYCR1 or ALDH18A1 may be a novel therapeutic strategy to target HCC. Even with the recently approved immunotherapies against liver cancer, currently available medications show limited clinical benefits or efficacy in the majority of patients. As such, it remains a top priority to discover new targets for effective liver cancer treatment. Here, we identify a critical role for the proline biosynthetic pathway in liver cancer development, and demonstrate that targeting key proteins in the pathway, namely PYCR1 and ALDH18A1, may be a novel therapeutic strategy for liver cancer. [Display omitted] •The proline biosynthesis pathway is altered in HCC tumors.•PYCR1 and ALDH18A1 are upregulated in HCC tumors.•Inhibition of PYCR1 or ALDH18A1 leads to reduced tumor burden.•PYCR1 and ALDH18A1 are independent predictors of HCC patient survival.•PYCR1 and ALDH18A1 may be novel therapeutic targets in liver cancer.