Metabolic reprogramming induced by ketone bodies diminishes pancreatic cancer cachexia

Abstract

BackgroundAberrant energy metabolism is a hallmark of cancer. To fulfill the increased energy requirements, tumor cells secrete cytokines/factors inducing muscle and fat degradation in cancer patients, a condition known as cancer cachexia. It accounts for nearly 20% of all cancer-related deaths. However, the mechanistic basis of cancer cachexia and therapies targeting cancer cachexia thus far remain elusive. A ketogenic diet, a high-fat and low-carbohydrate diet that elevates circulating levels of ketone bodies (i.e., acetoacetate, β-hydroxybutyrate, and acetone), serves as an alternative energy source. It has also been proposed that a ketogenic diet leads to systemic metabolic changes. Keeping in view the significant role of metabolic alterations in cancer, we hypothesized that a ketogenic diet may diminish glycolytic flux in tumor cells to alleviate cachexia syndrome and, hence, may provide an efficient therapeutic strategy.ResultsWe observed reduced glycolytic flux in tumor cells upon treatment with ketone bodies. Ketone bodies also diminished glutamine uptake, overall ATP content, and survival in multiple pancreatic cancer cell lines, while inducing apoptosis. A decrease in levels of c-Myc, a metabolic master regulator, and its recruitment on glycolytic gene promoters, was in part responsible for the metabolic phenotype in tumor cells. Ketone body-induced intracellular metabolomic reprogramming in pancreatic cancer cells also leads to a significantly diminished cachexia in cell line models. Our mouse orthotopic xenograft models further confirmed the effect of a ketogenic diet in diminishing tumor growth and cachexia.ConclusionsThus, our studies demonstrate that the cachectic phenotype is in part due to metabolic alterations in tumor cells, which can be reverted by a ketogenic diet, causing reduced tumor growth and inhibition of muscle and body weight loss.

Scientific rationale for integrative and personalised strategies for pancreatic ductal adenocarcinoma management

“…CR, which prevents or reverse obesity, improves insulin sensitivity, and inhibits the development and progression of a variety of cancer including PDAC [280,281]. CR regimen in PDAC decreases circulating levels of leptin and IGF-1, reduces expression of Glut1, suppresses activation of Akt/mTOR, ERK, STAT3, NF-κB and activates AMPK and SIRT1 [281][282][283] KD, is described as a high-fat and low carbohydrate diet that elevates circulating levels of ketone bodies, serving as an alternative energy source [284] Shukla et al [284] identified that ketone bodies revert metabolic adaptations in PDAC cells to induce growth arrest and apoptosis. Treatment with ketone bodies lead to a a reduction in glucose uptake, glycolytic flux, glutamine uptake, lactate secretion and ATP content in PDAC cells.…”

“…Treatment with ketone bodies lead to a a reduction in glucose uptake, glycolytic flux, glutamine uptake, lactate secretion and ATP content in PDAC cells. 284 Importantly, metabolic reprogramming of tumour cells by ketone bodies is responsible for diminishing cancer cell-induced cachexia in both cell line models and animal models of PDAC. 284 In addition, keeping in view the significant role of inflammation and metabolic alteration, a ketogenic diet also provides an efficient therapeutic strategy, because lowering lactate production by ketogenic diet has been shown to decrease MDSC frequency leading to improved antitumour immune response.285 Remarkably, a ketogenic diet causes minimal side effects as previously demonstrated that a 2-7 mM ketone body concentration can be achieved without giving rise to clinical acidosis.…”

“…284 Importantly, metabolic reprogramming of tumour cells by ketone bodies is responsible for diminishing cancer cell-induced cachexia in both cell line models and animal models of PDAC. 284 In addition, keeping in view the significant role of inflammation and metabolic alteration, a ketogenic diet also provides an efficient therapeutic strategy, because lowering lactate production by ketogenic diet has been shown to decrease MDSC frequency leading to improved antitumour immune response.285 Remarkably, a ketogenic diet causes minimal side effects as previously demonstrated that a 2-7 mM ketone body concentration can be achieved without giving rise to clinical acidosis. 286 Recalling the fact that, at the time of diagnosis around 80% of patients with PDAC present cachexia, ketogenic diet might serve as an anti-cachectic agent as well as an anti-cancer agent.…”

“…286 Recalling the fact that, at the time of diagnosis around 80% of patients with PDAC present cachexia, ketogenic diet might serve as an anti-cachectic agent as well as an anti-cancer agent. [284][285][286] …”

Fasting, Fats, and Physics: Combining Ketogenic and Radiation Therapy against Cancer

“…Studies using FDG-PET imaging [25,80] or microdialysis measurements [81] have shown that a KD can downregulate the glycolytic tumor metabolism in some patients. A decrease in tumor lactate production has also been observed in mice kept on a KD [82,83] and in cultured cancer cells treated with ketone bodies [84,85] or fasting-mimicking conditions [86,87]. The decreased tumor lactate concentrations after a few days on a KD in head-and-neck cancer patients measured by Schroeder et al [81] are of particular interest, as tumor lactate concentrations have been directly linked to radioresistance in a variety of xenografted head-and-neck tumors that were irradiated using a clinically relevant schedule of 30 fractions over 6 weeks [88,89].…”