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.
Highlights
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a classical protein with enormous biochemical and biophysical interests owing to its functional significance in glucose metabolism
Functional impairment of normal liver by hepatitis, excessive alcohol consumption, and aflatoxin B, in addition to oncogenic driver mutations, are considered as some of the causal factors that promote cirrhosis eventually leading to liver cancer [e.g. hepatocellular carcinoma (HCC)] (Figure 1)
The asymptomatic nature of HCC and the lack of an early-detection marker invariably result in the diagnosis of the disease at an advanced stage enforcing the patients to other treatment modalities
Summary
Liver cancer is one of the most lethal malignancies and consistently ranked as the third most common cause of cancer-related death worldwide [7] Intense research both at preclinical and clinical levels contributed a wealth of information on the causes and risk factors of liver cancer. Current curative therapies include surgical resection and transplantation, and are very effective in early-stage disease, very few patients qualify for such treatments. The asymptomatic nature of HCC and the lack of an early-detection marker invariably result in the diagnosis of the disease at an advanced stage enforcing the patients to other treatment modalities. As HCC is always associated with an underlying disease, it is imperative to administer any novel agent that selectively targets tumor cells with a high level molecular specificity. There has been a tremendous progress in the development of various therapeutics targeting different pathways or molecules of HCC[16, 17], yet the therapeutic success is often counteracted by chemoresistance and tumor recurrence necessitating the search for sensitive target molecule(s) that can be effectively targeted by potent inhibitors/drugs
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