• Vishnu Suresh Babu, Ashwin Mallipatna, Gagan Dudeja, Rohit Shetty, Archana Padmanabhan Nair, Sai Bo Bo Tun, Candice Ee Hua Ho, Shyam S Chaurasia, Shomi S Bhattacharya, Navin Kumar Verma, Rajamani Lakshminarayanan, Nilanjan Guha, Stephane Heymans, Veluchamy Amutha Barathi, and Arkasubhra Ghosh.
• GROW Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India; Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
• Transl Res. 2023 Nov 1; 261: 415641-56.

AbstractLack of retinoblastoma (Rb) protein causes aggressive intraocular retinal tumors in children. Recently, Rb tumors have been shown to have a distinctly altered metabolic phenotype, such as reduced expression of glycolytic pathway proteins alongside altered pyruvate and fatty acid levels. In this study, we demonstrate that loss of hexokinase 1(HK1) in tumor cells rewires their metabolism allowing enhanced oxidative phosphorylation-dependent energy production. We show that rescuing HK1 or retinoblastoma protein 1 (RB1) in these Rb cells reduced cancer hallmarks such as proliferation, invasion, and spheroid formation and increased their sensitivity to chemotherapy drugs. Induction of HK1 was accompanied by a metabolic shift of the cells to glycolysis and a reduction in mitochondrial mass. Cytoplasmic HK1 bound Liver Kinase B1 and phosphorylated AMP-activated kinase-α (AMPKα Thr172), thereby reducing mitochondria-dependent energy production. We validated these findings in tumor samples from Rb patients compared to age-matched healthy retinae. HK1 or RB1 expression in Rb-/- cells led to a reduction in their respiratory capacity and glycolytic proton flux. HK1 overexpression reduced tumor burden in an intraocular tumor xenograft model. AMPKα activation by AICAR also enhanced the tumoricidal effects of the chemotherapeutic drug topotecan in vivo. Therefore, enhancing HK1 or AMPKα activity can reprogram cancer metabolism and sensitize Rb tumors to lower doses of existing treatments, a potential therapeutic modality for Rb.Copyright © 2023 Elsevier Inc. All rights reserved.

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