Lack of Retinoblastoma Protein Shifts Tumor Metabolism from Glycolysis to OXPHOS and Allows the Use of Alternate Fuels
Vishnu Suresh Babu,Gagan Dudeja,Deepak Sa,Anadi Bisht,Rohit Shetty,Stephane Heymans,Nilanjan Guha,Arkasubhra Ghosh +7 more
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TLDR
RB1 or HK1 are demonstrated as critical regulators of the cellular bioenergetic profile and identify the altered tumor metabolism as a potential therapeutic target for cancers lacking functional Rb protein.Abstract:
Mutations in the RB1 locus leading to a loss of functional Rb protein cause intraocular tumors, which uniquely affect children worldwide. These tumors demonstrate rapid proliferation, which has recently been shown to be associated with an altered metabolic signature. We found that retinoblastoma tumors and in-vitro models lack Hexokinase 1 (HK1) and exhibit elevated fatty acid oxidation. We show that ectopic expression of RB1 induces HK1 protein in Rb null cells, and both RB1 and HK1 can mediate a metabolic switch from OXPHOS to glycolysis with increased pyruvate levels, reduced ATP production and reduced mitochondrial mass. Further, cells lacking Rb or HK1 can flexibly utilize glutamine and fatty acids to enhance oxidative phosphorylation-dependent ATP generation, as revealed by metabolic and biochemical assays. Thus, loss of Rb and HK1 in retinoblastoma reprograms tumor metabolic circuits to enhance the glucose-independent TCA (tricarboxylic acid) cycle and the intermediate NAD+/NADH ratios, with a subsequent increase in fatty-acid derived L-carnitine to enhance mitochondrial OXPHOS for ATP production instead of glycolysis dependence. We also demonstrate that modulation of the Rb-regulated transcription factor E2F2 does not result in any of these metabolic perturbations. In conclusion, we demonstrate RB1 or HK1 as critical regulators of the cellular bioenergetic profile and identify the altered tumor metabolism as a potential therapeutic target for cancers lacking functional Rb protein.read more
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Selective Induction of Intrinsic Apoptosis in Retinoblastoma Cells by Novel Cationic Antimicrobial Dodecapeptides
Vishnu Suresh Babu,Atish Kizhakeyil,Gagan Dudeja,Shyam S Chaurasia,Veluchami Amutha Barathi,Stephane Heymans,Navin Kumar Verma,Rajamani Lakshminarayanan,Arkasubhra Ghosh +8 more
TL;DR: In this paper , a panel of hypercharged wholly cationic antimicrobial dodecapeptides (CAPs) containing multiple canonical forms of lysine and arginine residues was used to destroy retinoblastoma cells.
Journal ArticleDOI
The role of EZH2 as a potential therapeutic target in retinoblastoma.
Yuqing Zhao,Ying Cheng,Yi Qu +2 more
TL;DR: In this paper , immunohistochemistry (IHC) was performed on tumor specimens from 53 human retinoblastoma (RB) patients to assess the role and mechanism of EZH2 in RB proliferation, metastasis and tumor glycolysis.
Journal ArticleDOI
Depleted Hexokinase1 and lack of AMPKα activation favor OXPHOS-dependent energetics in Retinoblastoma tumors.
Vishnu Suresh Babu,Ashwin Mallipatna,Gagan Dudeja,Rohit Shetty,Archana Padmanabhan Nair,Sai Bo Bo Tun,Candice E H Ho,Shyam S Chaurasia,Shomi S. Bhattacharya,Navin Kumar Verma,Rajamani Lakshminarayanan,Nilanjan Guha,Stephane Heymans,Veluchamy A. Barathi,Arkasubhra Ghosh +14 more
TL;DR: In this paper , the authors demonstrate that loss of Hexokinase 1(HK1) in tumor cells rewires their metabolism allowing enhanced oxidative phosphorylation-dependent energy production.
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