Tumor Cells Switch to Mitochondrial Oxidative Phosphorylation under Radiation via mTOR-Mediated Hexokinase II Inhibition - A Warburg-Reversing Effect

Abstract

A unique feature of cancer cells is to convert glucose into lactate to produce cellular energy, even under the presence of oxygen. Called aerobic glycolysis [The Warburg Effect] it has been extensively studied and the concept of aerobic glycolysis in tumor cells is generally accepted. However, it is not clear if aerobic glycolysis in tumor cells is fixed, or can be reversed, especially under therapeutic stress conditions. Here, we report that mTOR, a critical regulator in cell proliferation, can be relocated to mitochondria, and as a result, enhances oxidative phosphorylation and reduces glycolysis. Three tumor cell lines (breast cancer MCF-7, colon cancer HCT116 and glioblastoma U87) showed a quick relocation of mTOR to mitochondria after irradiation with a single dose 5 Gy, which was companied with decreased lactate production, increased mitochondrial ATP generation and oxygen consumption. Inhibition of mTOR by rapamycin blocked radiation-induced mTOR mitochondrial relocation and the shift of glycolysis to mitochondrial respiration, and reduced the clonogenic survival. In irradiated cells, mTOR formed a complex with Hexokinase II [HK II], a key mitochondrial protein in regulation of glycolysis, causing reduced HK II enzymatic activity. These results support a novel mechanism by which tumor cells can quickly adapt to genotoxic conditions via mTOR-mediated reprogramming of bioenergetics from predominantly aerobic glycolysis to mitochondrial oxidative phosphorylation. Such a “waking-up” pathway for mitochondrial bioenergetics demonstrates a flexible feature in the energy metabolism of cancer cells, and may be required for additional cellular energy consumption for damage repair and survival. Thus, the reversible cellular energy metabolisms should be considered in blocking tumor metabolism and may be targeted to sensitize them in anti-cancer therapy.

CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation

“…Importantly, the contributions of FAO (31,32) and OxPhos (50) to TNBC migration and metastasis and OxPhos to metastasis of other cancers (55,56) have been recently documented, supporting our proposed mechanism. Accordingly, pharmacological and genetic inhibitors of carnitine palmitoyltransferases blocked lipid transport to mitochondria, FAO, OxPhos, and metastasis of TNBC cells (31,32).…”

Modeling the Genetic Regulation of Cancer Metabolism: Interplay between Glycolysis and Oxidative Phosphorylation

“…The activation of oncogenic pathways is an alternative way to induce cells to lie in the hybrid state. The discovery of the hybrid metabolic state for cancer cells from the network analysis has been supported by recent experimental evidence (10, 11, 16, 19, 20) (summarized in Table S1). The association of cancer metabolism and oncogenic pathways are also supported by extensive TCGA and single-cell transcriptomics data analysis of multiple cancer types under this theoretical framework.…”

Metabolism of Preimplantation Embryo Development

“…Intriguingly, in addition to serving as an energy source, amino acids may have the ability to induce favorable energy metabolism during preimplantation embryo development: in the absence of amino acids, preimplantation embryos display upregulation of glycolysis and downregulation of OXPHOS during blastocyst formation, whereas in the presence of amino acids in the culture media, embryos downregulate glycolysis and upregulate OXPHOS, mimicking the energy metabolism observed in freshly isolated blastocysts (Lane & Gardner, 1994, 1996. As described in the first section, amino acids have the capacity to modulate OXPHOS in a number of ways including their ability to enter the TCA cycle for energy production, as well as their ability to upregulate OXPHOS through the mTOR pathway (Lu et al, 2015;Ramanathan & Schreiber, 2009). As both glutamine and leucine play crucial roles in activating mTOR (Nicklin et al, 2009), the effects of amino acids in preimplantation development may be mediated partly through mTOR signaling.…”