Reprogramming of amino acid metabolism in cholangiocarcinoma: A potential target for metabolic-targeted therapy

Abstract

The incidence of cholangiocarcinoma (CCA), a highly aggressive malignancy of the bile duct epithelia, has been gradually increasing worldwide. However, curative treatments are still limited. Novel therapeutic strategies are urgently needed to improve patients’ survival and quality of life. Metabolic reprogramming has been well recognized as one of the hallmark processes supporting the development of several cancer types, including CCA. Apart from the Warburg effect and high glucose requirement in CCA cells, amino acid metabolism is also found to be essential in CCA development and progression. Upregulation of proteins and enzymes involved in amino acid metabolism is reported in CCA, typically associated with a poor prognosis for patients. Targeting these proteins and enzymes has been shown to retard CCA progression, and thus, they are promising targets for drug development. This article reviews the reprogramming of amino acid metabolism in CCA and its roles in CCA progression, such as aggressive phenotypes. The up-to-date development of therapeutic agents targeting particular proteins in amino acid metabolism is also discussed. A summary of the current knowledge gap and directions for further research are also provided and proposed.

Keywords: Amino acid; Biliary tract cancer; Cancer metabolism; Cholangiocarcinoma; Metabolic reprogramming

Core Tip: Metabolic reprogramming is a malignant hallmark found in many types of cancer, including cholangiocarcinoma (CCA). A higher requirement and dependency of certain amino acids is found in CCA and is generally associated with aggressive phenotypes of cancer cells, leading to poor prognosis of patients. In this article, amino acids with reports of their significance in CCA development and progression are reviewed. The mechanisms underlying amino acid metabolic reprogramming and their networks with intracellular signaling are also discussed. Up-to-date interventions and the opportunity for metabolic targeting in CCA treatment are proposed.