Role of TCA cycle Truncation in Cancer Cell Energetics

Order of Publishing in Issue: 
11
Volume :8
Issue :4
October, 2014
Page No: 
428-438
Authors: 
Vikrant Nain, Richa Buddham, Rekha Puria and Shakti Sahi [*]
Address: 
School of Biotechnology, Gautam Buddha University, Greater Noida -201312, India
Email-ID: 
shaktis@gbu.ac.in

Continuously dividing cancerous cell requires duplication of its genome and other cellular building blocks before every cell division. This increased demand for amino acids, nucleotides and fatty acids, require readjustment of metabolic pathways, specially glycolysis and TCA cycle, to divert intermediates of these series of reactions from energy generating process (OXPHOS) to synthesis of cellular macromolecule building blocks. This altered cellular metabolism has been observed as early as 1926. Otto Warburg observed aerobic glycolysis and proposed defective mitochondria as a cause of cancer. Since then, ‘Warburg effect’ has become a hallmark of cancer detection by positron emission tomography (PET) and is now being perused for designing of novel anticancer drug targeting enzymes like PKM2. However, since beginning, Warburg hypothesis of nonfunctional mitochondria has been questioned. Now it is clear that cancerous cell has intact and functional mitochondria, moreover reverse. Warburg effect has proposed a nonfunctional mitochondria in stromal tissue and with functional OXPHOS system for ATP synthesis in cancerous cells. These two hypotheses of Warburg and reverse Warburg show two extremes one relying almost completely on aerobic glycolysis and another on OXPHOS for ATP synthesis in cancerous cell, but both of them fail to explain how cell readjusts to meet increased demand for ATP synthesis as well as cellular building blocks simultaneously, from the intermediates of glycolysis and TCA cycle. In the present hypothesis, we present how truncation of TCA cycle can increase rate of synthesis of amino acids and simultaneously TCA cycle gets completed to generate NADH and FADH2. Oncomine database analysis further shows upregulation of ATP synthase genes and indicative of increased OXPHOS I cancerous cell. In this background, we propose that cancerous cell utilizes both aerobic glycolysis and OXPHOS, for synthesis of ATP and to meet increased requirement of proteins, nucleic acids and fatty acids.

Keywords: 
Metabolic rearrangement, onco genomics, oncogenic mutations, TCA cycle, ROS.
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