Glyceraldehyde-3-Phosphate Dehydrogenase: A Promising Target for Molecular Therapy in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most highly lethal malignancies ranking as the third leading-cause of cancer-related death worldwide. Although surgical resection and transplantation are effective curative therapies, very few patients qualify for such treatments due to the advanced stage of the disease at diagnosis. In this context, loco-regional therapies provide a viable therapeutic alternative with minimal systemic toxicity. However, as chemoresistance and tumor recurrence negatively impact the success of therapy resulting in poorer patient outcomes it is imperative to identify new molecular target(s) in cancer cells that could be effectively targeted by novel agents. Recent research has demonstrated that proliferation in HCC is associated with increased glucose metabolism. The glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a multifunctional protein primarily recognized for its role in glucose metabolism, has already been shown to affect the proliferative potential of cancer cells. In human HCC, the increased expression of GAPDH is invariably associated with enhanced glycolytic capacity facilitating tumor progression. Though it is not yet known whether GAPDH up-regulation contributes to tumorigenesis sensu stricto, emerging evidence points to the existence of a link between GAPDH up-regulation and the promotion of survival mechanisms in cancer cells as well as chemoresistance. The involvement of GAPDH in several hepatocarcinogenic mechanisms (e.g. viral hepatitis, metabolic alterations) and its sensitivity to a new class of prospective anticancer agents prompted us to review the current understanding of the therapeutic potential of targeting GAPDH in HCC.

Glyceraldehyde-3-phosphate dehydrogenase is overexpressed in colorectal cancer onset

“…Non-tumour cells are expected to be less sensitive to glycolysis inhibition than malignant cells, which are more dependent on this pathway to generate ATP and proliferate [34]. Therefore, GAPDH emerges as a promising therapeutic target against cancer since it is overexpressed in 21 cancer classes [3] and involved not only in cell proliferation and glycolysis but also in several other mechanisms which are upregulated in tumour cells [35,36].…”

Targeting glucose metabolism in cancer: a new class of agents for loco-regional and systemic therapy of liver cancer and beyond?

“…Its ability to deactivate GAPDH was first described in the year 1993 and autographic evidence was provided in 2010 [49,50]. As a multifunctional enzyme that is often upregulated in cancer cells, GAPDH is reported to support tumorigenesis and chemoresistance and therefore constitutes a promising target for antitumoral therapy [51,52].…”

Selection of reference genes for RT-qPCR analysis in tumor tissues from male hepatocellular carcinoma patients with hepatitis B infection and cirrhosis

“…Separate studies even suggested that GAPDH expression was correlated with chemotherapy-induced DNA damage response in vitro [12][13][14]. A study even suggested the heavily regulation of GAPDH during HCC carcinogenesis and progression in patients with HBV related HCC [15], as it can affect the proliferative potential of cancer cells in HCC [16]. HBV infection, the presence of cirrhosis and male gender are repeatedly recognized as the independent risk factors for the development of HCC [17][18][19].…”