Natural product-derived therapy for Hepatocellular carcinoma: δ-tocotrienol (a form of Vitamin-E) attenuates phosphoenolpyruvate carboxykinase (PEPCK1) sumoylation, stabilizes PEPCK1 levels, promotes gluconeogenesis, inhibits glycolysis and attenuates the progression of hepatocellular carcinoma via up regulation of its target gene, 7/March/2017, 2.27 pm

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Introduction: What they say:

A study from the State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian Province, Xiamen 361102, China” shows that “Nur77 suppresses hepatocellular carcinoma via switching glucose metabolism toward gluconeogenesis through attenuating phosphoenolpyruvate carboxykinase sumoylation.” This study was published in the 27 January 2017 issue of the journal “Nature communications” [the number 1 journal in General Biology with an I.F of plus 11.329] by Prof. Qiao Wu, Xue-li Bian, and others.


What we say:

On the foundation of this interesting finding, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that: Natural product-derived therapy for Hepatocellular carcinoma: δ-tocotrienol (a form of Vitamin-E) attenuates phosphoenolpyruvate carboxykinase (PEPCK1) sumoylation, stabilizes PEPCK1 levels, promotes gluconeogenesis, inhibits glycolysis and attenuates the progression of hepatocellular carcinoma via up regulation of its target gene


From Significance of the study to Public health relevance:

Given that: (i) each year nearly 14 million people are diagnosed with cancer globally, and little more than half of them will die; (ii) Hepatocellular carcinoma is one of the most common human tumors; (iii) Hepatocellular carcinoma causes more than 6 million deaths worldwide per year; (iv) cancer deaths globally are expected to be doubled by 2030; (v) cancer treatment causes the highest economic loss compared to all the known causes of death worldwide, there is an urgent need to find: (i) a way to activate immune system to combat cancer (Cancer immunotherapy); (ii) anticancer drugs that target cancer stem cells that aid in tumor relapse and resistance; (iii) a cheaper alternative to the existing expensive anticancer drugs; (iv) a side-effect-free natural product-based drug; (v) increase the therapeutic index of anti-cancer drugs; and (vi) a way to effectively treat and prevent metastatic progression and relapse of advanced/drug-resistant cancers.


What we infer from what they say:

Prof.Qiao Wu’s research team has recently shown that Nur77: (1) attenuates sumoylation of the rate-limiting enzyme in gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK1); (2) prevents PEPCK1 degradation via ubiquitination; (3) stabilizes PEPCK1; (4) increases the expression of gluconeogenic genes, such as G6pc, Fbp1 and Fbp2, and Eno3; (5) decreases glycolysis; (6) impairs ATP levels; and (7) inhibits hepatocellular carcinoma development. Further, they have shown that: (1) the EMT protein Snail inhibits Nur77 expression via DNA hypermethylation and histone acetylation; and (2) NUR77 is silenced in human HCC.


From research findings to therapeutic opportunity :

This study suggests a natural product-derived therapy for Hepatocellular carcinoma. δ-tocotrienol has been shown to function as an anticancer agent (fig. 1). However, the detailed mechanistic insights is yet to emerge.

δ-tocotrienol, by increasing the expression of its target genes, it may increase the expression of NUR77 (fig. 1). Thereby, it may: (i) prevent sumoylation of PEPCK1; (ii) stabilize PEPCK1 (disrupt the Ubc9-PEPCK1 interaction through down regulation of p300 activity); (iii) increase the expression of gluconeogenic genes such as G6pc, Fbp1 and Fbp2, and Eno3; (iv) increase gluconeogenesis, while attenuating glycolysis; (v) decrease ATP levels; and (vi) stall hepatocellular carcinoma development. Thus, pharmacological formulations encompassing δ-tocotrienol or its analogues either alone or in combination with other known anticancer drugs” (fig. 1) may be used to inhibit HCC progression.

 increases NUR77 expression

Figure 1. Mechanistic insights into how δ-tocotrienol (a form of Vitamin-E) functions as an anticancer agent in Hepatocellular carcinoma.

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Details of the Research findings:

Idea Proposed/Formulated (with experimental evidence) by: Dr L Boominathan Ph.D.

Amount: $500#

Undisclosed mechanistic information: How does δ-tocotrienol increase the expression of PEPCK1, G6pc, Fbp1 and Fbp2, and Eno3 to inhibit hepatocellular carcinoma development?

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References:

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Citation: Boominathan, L., Natural product-derived therapy for Hepatocellular carcinoma: δ-tocotrienol (a form of Vitamin-E) attenuates phosphoenolpyruvate carboxykinase (PEPCK1) sumoylation, stabilizes PEPCK1 levels, promotes gluconeogenesis, inhibits glycolysis and attenuates the progression of hepatocellular carcinoma via up regulation of its target gene, 7/March/2017, 2.28 pm, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

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