Highlights
- •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.
Background & Aim
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.
Methods
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.
Results
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.
Conclusion
Enhanced expression of proline biosynthetic enzymes promotes HCC cell proliferation.
Inhibition of PYCR1 or ALDH18A1 may be a novel therapeutic strategy to target HCC.
Lay summary
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.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: November 11, 2019
Accepted:
October 28,
2019
Received in revised form:
October 24,
2019
Received:
December 3,
2018
Identification
Copyright
© 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
