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Review
, 3 (9), 940-53

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

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Review

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

Shanmugasundaram Ganapathy-Kanniappan et al. Oncotarget.

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.

Figures

Figure 1
Figure 1. A schematic representation showing the transformation of normal liver into cirrhotic liver leading to HCC
Figure 2
Figure 2. A schematic showing the involvement of GAPDH in hepatocarcinogenic mechanisms
Figure 3
Figure 3. Overall view of the homotetramer of human liver GAPDH [44] (Reproduced with permission from http://dx.doi.org/10.1107/S0907444905026740)
Figure 4
Figure 4. Structure of various inhibitors of GAPDH with anticancer effects in preclinical models (Reproduced with permission of RSC Worldwide Ltd from http://www.chemspider.com)
Figure 5
Figure 5. A schematic diagram showing the involvement of GAPDH in the processes related to the initiation/ promotion and progression of hepatocarcinogenesis
Figure 6
Figure 6. Human liver GAPDH showing various motifs
(A). Line diagram showing the N-terminal and C-terminal regions with Cysteine residues (red bars). The amino acid residues numbered as 152 to 156 correspond to the catalytic site. Note: two cysteine residues located in the catalytic site are sensitive targets for majority of the GAPDH inhibitors. (B). The peptide sequence of GAPDH subunit indicating various posttranslational modification sites. Circles (○) represent Glyceraldehyde-3 phosphate binding sites; Square Boxes (□) represent NAD binding sites; Red font represents phosphoserine sites; Blue font represents phosphothreonine sites; Pink font represents aminoacid residue that Activates thiol group during catalysis; Green font represents phosphotyrosine sites; Purple font represents Predicted Sumoylation sites (70-90% probability); Italic font represents S-nitrosylation site and Underlined font represents SIAH-1 binding site. Arrow-head (↑) indicates predicted methylation sites while the with Down-ward Arrow (↓) indicates acetylation sites. Region 2-148 is the domain involved in the interaction WARS (tryptophan-tRNA ligase).

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