Metabolic regulation of cancer cell proliferation and resistance to temozolomide chemotherapy

Cancers are characterized by unbridled cell proliferation. To sustain the bioenergetic and biosynthetic requirements for high rate proliferation, cancer cells rely on a variety of metabolic substrates, among which glutamine. During this work, we found that this amino acid activates transcription factor STAT3, which is necessary and sufficient to ensure cancer cell proliferation and associated metabolic changes. We further studied the possibility of a metabolic resistance to chemotherapy in the context of glioblastoma treated by temozolomide (TMZ). Hence, we discovered that acquired resistance to TMZ is associated with a switch to a more glycolytic metabolism, which however did not cause resistance. Rather, we found that TMZ-resistant cells have a high basal activation of DNA repair mechanism and the capability to escape cell cycle checkpoints.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201

Polyunsaturated fatty acids, polyphenols, amino acids, prebiotics: can they help to tackle cancer cachexia and related inflammation?

PURPOSE OF REVIEW: Recent studies have highlighted the importance of developing a multimodal therapeutic strategy for cancer cachectic patients. Considering the central role of metabolism and anorexia in this disease, optimized nutritional advice should be an integral part of this strategy. Current recommendations mainly focus on meeting caloric requirements. However, a few studies suggest the great potential of foods naturally enriched in nutrients presenting interesting physiological properties and the interest of using them in the management of cachectic patients. Among them, prebiotics shows the capacity to control inflammation in several debilitating diseases. In this context, this review aims to summarize the most recent findings related to functional foods and nutrients and cancer cachexia, and to discuss the potential use of prebiotics in this context. RECENT FINDINGS: Even though there is a clear need for more research in the field, data from both humans and animal models support the promising benefits of functional foods and nutrients in cancer cachexia. SUMMARY: Altogether, these studies offer new insights into the potential contribution of nutrition to cancer patient management. Functional foods, by downregulating inflammatory pathways, could decrease cachexia severity and contribute to the improvement of cancer patients' quality of life

Glutamine activates STAT3 to control cancer cell proliferation independently of glutamine metabolism

Cancer cells can use a variety of metabolic substrates to fulfill the bioenergetic and biosynthetic needs of their oncogenic program. Besides bioenergetics, cancer cell metabolism also directly influences genetic, epigenetic and signaling events associated with tumor progression. Many cancer cells are addicted to glutamine, and this addiction is observed in oxidative as well as in glycolytic cells. While both oxidative and bioreductive glutamine metabolism can contribute to cancer progression and glutamine can further serve to generate peptides (including glutathione) and proteins, we report that glutamine promotes the proliferation of cancer cells independently of its use as a metabolic fuel or as a precursor of glutathione. Extracellular glutamine activates transcription factor STAT3, which is necessary and sufficient to mediate the proliferative effects of glutamine on glycolytic and in oxidative cancer cells. Glutamine also activates transcription factors HIF-1, mTOR and c-Myc, but these factors do not mediate the effects of glutamine on cancer cell proliferation. Our findings shed a new light on the anticancer effects of L-asparaginase that possesses glutaminase activity and converts glutamine into glutamate extracellularly. Conversely, cancer resistance to treatments that block glutamine metabolism could arise from glutamine-independent STAT3 re-activation

Energy metabolism in osteoclast formation and activity.

Osteoclastogenesis and osteolysis are energy-consuming processes supported by high metabolic activities. In human osteoclasts derived from the fusion of monocytic precursors, we found a substantial increase in the number of mitochondria with differentiation. In mature osteoclasts, mitochondria were also increased in size, rich of cristae and arranged in a complex tubular network. When compared with immature cells, fully differentiated osteoclasts showed higher levels of enzymes of the electron transport chain, a higher mitochondrial oxygen consumption rate and a lower glycolytic efficiency, as evaluated by extracellular flux analysis and by the quantification of metabolites in the culture supernatant. Thus, oxidative phosphorylation appeared the main bioenergetic source for osteoclast formation. Conversely, we found that bone resorption mainly relied on glycolysis. In fact, osteoclast fuelling with galactose, forcing cells to depend on Oxidative Phosphorylation by reducing the rate of glycolysis, significantly impaired Type I collagen degradation, whereas non-cytotoxic doses of rotenone, an inhibitor of the mitochondrial complex I, enhanced osteoclast activity. Furthermore, we found that the enzymes associated to the glycolytic pathway are localised close to the actin ring of polarised osteoclasts, where energy-demanding activities associated with bone degradation take place. In conclusion, we demonstrate that the energy required for osteoclast differentiation mainly derives from mitochondrial oxidative metabolism, whereas the peripheral cellular activities associated with bone matrix degradation are supported by glycolysis. A better understanding of human osteoclast energy metabolism holds the potential for future therapeutic interventions aimed to target osteoclast activity in different pathological conditions of bone

Lactate stimulates CA IX expression in normoxic cancer cells

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