Abstract
Aerobic glycolysis is essential for supporting the fast growth of a variety of cancers. However, its role in the survival of cancer cells under stress conditions is unclear. We have previously reported an efficient model of gammaherpesvirus Kaposi’s sarcoma-associated herpesvirus (KSHV)-induced cellular transformation of rat primary mesenchymal stem cells. KSHV-transformed cells efficiently induce tumors in nude mice with pathological features reminiscent of Kaposi’s sarcoma tumors. Here, we report that KSHV promotes cell survival and cellular transformation by suppressing aerobic glycolysis and oxidative phosphorylation under nutrient stress. Specifically, KSHV microRNAs and vFLIP suppress glycolysis by activating the NF-κB pathway to downregulate glucose transporters GLUT1 and GLUT3. While overexpression of the transporters rescues the glycolytic activity, it induces apoptosis and reduces colony formation efficiency in softagar under glucose deprivation. Mechanistically, GLUT1 and GLUT3 inhibit constitutive activation of the AKT and NF-κB pro-survival pathways. Strikingly, GLUT1 and GLUT3 are significantly downregulated in KSHV-infected cells in human KS tumors. Furthermore, we have detected reduced levels of aerobic glycolysis in several KSHV-infected primary effusion lymphoma cell lines compared to a Burkitt’s lymphoma cell line BJAB, and KSHV infection of BJAB cells reduced aerobic glycolysis. These results reveal a novel mechanism by which an oncogenic virus regulates a key metabolic pathway to adapt to stress in tumor microenvironment, and illustrate the importance of fine-tuning the metabolic pathways for sustaining the proliferation and survival of cancer cells, particularly under stress conditions.
Highlights
It has been recognized that metabolic reprogramming is a core hallmark of cancer[1]
To determine the metabolic state of KSHVtransformed cells, we examined the consumption of glucose, the main carbon source for most normal and cancer cells
Glucose flows through glycolysis and tricarboxylic acid (TCA) cycle to generate ATP and NADH with the latter further serving as a substrate for oxidative phosphorylation to produce additional ATP, a process that consumes oxygen[4]
Summary
It has been recognized that metabolic reprogramming is a core hallmark of cancer[1]. The Warburg effect describes the dependence of cancer cells on aerobic glycolysis for their growth and proliferation[2]. Increased glucose uptake and aerobic glycolysis are widely observed in cancer and clinically exploited for diagnosis[3]. Aerobic glycolysis provides a fast supply of ATP to support the rapid growth and proliferation of cancer cells[3]. Recent works have shown that besides energy, cancer cells have special needs for macromolecular building blocks and maintenance of redox balance[4, 5]. Metabolic adaptation in cancer cells has been extended beyond the Warburg effect[5]. Several types of cancers depend on glutamine or one carbon amino acids for growth and proliferation[4, 5]
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