Elucidating the Metabolic Plasticity of Cancer: Mitochondrial Reprogramming and Hybrid Metabolic States

Abstract

Aerobic glycolysis, also referred to as the Warburg effect, has been regarded as the dominant metabolic phenotype in cancer cells for a long time. More recently, it has been shown that mitochondria in most tumors are not defective in their ability to carry out oxidative phosphorylation (OXPHOS). Instead, in highly aggressive cancer cells, mitochondrial energy pathways are reprogrammed to meet the challenges of high energy demand, better utilization of available fuels and macromolecular synthesis for rapid cell division and migration. Mitochondrial energy reprogramming is also involved in the regulation of oncogenic pathways via mitochondria-to-nucleus retrograde signaling and post-translational modification of oncoproteins. In addition, neoplastic mitochondria can engage in crosstalk with the tumor microenvironment. For example, signals from cancer-associated fibroblasts can drive tumor mitochondria to utilize OXPHOS, a process known as the reverse Warburg effect. Emerging evidence shows that cancer cells can acquire a hybrid glycolysis/OXPHOS phenotype in which both glycolysis and OXPHOS can be utilized for energy production and biomass synthesis. The hybrid glycolysis/OXPHOS phenotype facilitates metabolic plasticity of cancer cells and may be specifically associated with metastasis and therapy-resistance. Moreover, cancer cells can switch their metabolism phenotypes in response to external stimuli for better survival. Taking into account the metabolic heterogeneity and plasticity of cancer cells, therapies targeting cancer metabolic dependency in principle can be made more effective.

Towards Decoding the Metabolic Plasticity in Cancer: Coupling of Gene Regulation and Metabolic Pathways

“…Here, the AMPK activity is represented by the level of phosphorylated AMPK (pAMPK) at threonine-172 of the a subunit. The emergence of the hybrid metabolic phenotype of cancer cells from our modeling analysis has been supported by recent experimental evidence (10,12,13,16,17). We argued that the hybrid metabolic phenotype exhibits metabolic plasticity to adapt to varying microenvironments and hence tends to be more aggressive relative to cells in a more glycolysis or OXPHOS phenotype (13).…”

“…In addition, the hybrid metabolic phenotype maintains the cellular ROS at a moderate level so that cancer cells can benefit from ROS signaling (42) and still avoid DNA damage due to excessive ROS (43). Moreover, the hybrid metabolic phenotype may be specifically associated with metastasis (10,12,13,16,17) and the survival and propagation of therapy-resistance cancer stem cells (CSCs) [38][39][40]. As we showed in Fig.…”

Dynamic metabolic reprogramming in dendritic cells: an early response to influenza infection that is essential for effector function

“…However, palmitic acid oxidation was unchanged in IAV infected DC concomitant to a decrease in intracellular free fatty acids (Fig 2E & F). Together, the increase in glycolysis and decrease in TCA cycle utilization of pyruvate is reminiscent of the Warburg effect that occurs in some cancers, in which the two major metabolic pathways become uncoupled to maintain ATP production while increasing metabolic plasticity [31–36].…”

Nandrolone induces a stem cell-like phenotype in human hepatocarcinoma-derived cell line inhibiting mitochondrial respiratory activity

“…Moreover, cancer cells can switch their metabolism phenotypes in response to external stimuli for better survival. Likewise, many recent studies have implicated metabolic mechanisms as major regulators of pluripotent stem cells properties and mitochondrial functions as controller of stem cell maintenance/differentiation in several cell types [22][23][24][25][26][27] . To the best of our knowledge, no studies about androgens and ND influence on mitochondrial bioenergetic function in cancer cells have been reported so far.…”