Multiple Metabolic Alterations Exist in Mutant PI3K Cancers, but Only Glucose Is Essential as a Nutrient Source

Abstract

Targeting tumour metabolism is becoming a major new area of pharmaceutical endeavour. Consequently, a systematic search to define whether there are specific energy source dependencies in tumours, and how these might be dictated by upstream driving genetic mutations, is required. The PI3K-AKT-mTOR signalling pathway has a seminal role in regulating diverse cellular processes including cell proliferation and survival, but has also been associated with metabolic dysregulation. In this study, we sought to define how mutations within PI3KCA may affect the metabolic dependency of a cancer cell, using precisely engineered isogenic cell lines. Studies revealed gene expression signatures in PIK3CA mutant cells indicative of a consistent up-regulation of glycolysis. Interestingly, the genes up- and down-regulated varied between isogenic models suggesting that the primary node of regulation is not the same between models. Additional gene expression changes were also observed, suggesting that metabolic pathways other than glycolysis, such as glutaminolysis, were also affected. Nutrient dependency studies revealed that growth of PIK3CA mutant cells is highly dependent on glucose, whereas glutamine dependency is independent of PIK3CA status. In addition, the glucose dependency exhibited by PIK3CA mutant cells could not be overridden by supplementation with other nutrients. This specific dependence on glucose for growth was further illustrated by studies evaluating the effects of targeted disruption of the glycolytic pathway using siRNA and was also found to be present across a wider panel of cancer cell lines harbouring endogenous PIK3CA mutations. In conclusion, we have found that PIK3CA mutations lead to a shift towards a highly glycolytic phenotype, and that despite suggestions that cancer cells are adept at utilising alternative nutrient sources, PIK3CA mutant cells are not able to compensate for glucose withdrawal. Understanding the metabolic dependencies of PIK3CA mutant cancers will provide critical information for the design of effective therapies and tumour visualisation strategies.

Tissue metabolomics of hepatocellular carcinoma: Tumor energy metabolism and the role of transcriptomic classification

“…In a study of breast cancer and normal breast tissues, myo ‐inositol and glucose were lower in the tumor samples 45. The PI3K‐AKT‐mTOR pathway is perturbed in many cancers and it was recently reported that cell lines with mutated PI3K possess a highly glycolytic phenotype and withdrawal of glucose cannot be compensated by addition of alternative nutrients 44. Whether or not our observation of an ∼2‐fold attenuation of myo ‐inositol tumor concentrations (Fig.…”

“…Myo ‐inositol is a metabolic precursor of the inositol phosphate second messengers, phosphatidylinositol membrane lipids, and the phosphoinositide lipid signaling molecules 34. The PI3K‐AKT‐mTOR pathway, which has been associated with induction of aerobic glycolysis and tumor metabolic remodeling,43, 44 requires inositol triphosphate (PI3), and thus myo ‐inositol as a substrate. Myo ‐inositol is synthesized from glucose34 and thus diminution of cellular glucose by enhanced metabolism is likely to impact cellular myo ‐inositol.…”

Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype

“…An emphasis on the PI3K pathway was made because of the role of mTOR and other pathway components in glucose homeostasis (Elstrom et al, 2004;Sun et al, 2011). It has also been reported that PIK3CA mutant tumours have a high rate of glucose uptake and dependence on glycolysis (Cantley, 2012;Foster et al, 2012). GC cells were used because of the commonly hypoglycaemic state of gastric tumours (Hirayama et al, 2009).…”

Hypothermia Activates Adipose Tissue to Promote Malignant Lung Cancer Progression

“…Conventionally, the energy source driving cancer cell proliferation results from aerobic glycolysis [39]. It is now becoming increasingly clear that cancer arises as a consequence of dysregulated metabolism in response to an altered energy status and endocrine factors [40].…”