Targeting the Interplay between Cancer Metabolic Reprogramming and Cell Death Pathways as a Viable Therapeutic Path

In cancer cells, metabolic adaptations are often observed in terms of nutrient absorption, biosynthesis of macromolecules, and production of energy necessary to meet the needs of the tumor cell such as uncontrolled proliferation, dissemination, and acquisition of resistance to death processes induced by both unfavorable environmental conditions and therapeutic drugs. Many oncogenes and tumor suppressor genes have a significant effect on cellular metabolism, as there is a close relationship between the pathways activated by these genes and the various metabolic options. The metabolic adaptations observed in cancer cells not only promote their proliferation and invasion, but also their survival by inducing intrinsic and acquired resistance to various anticancer agents and to various forms of cell death, such as apoptosis, necroptosis, autophagy, and ferroptosis. In this review we analyze the main metabolic differences between cancer and non-cancer cells and how these can affect the various cell death pathways, effectively determining the susceptibility of cancer cells to therapy-induced death. Targeting the metabolic peculiarities of cancer could represent in the near future an innovative therapeutic strategy for the treatment of those tumors whose metabolic characteristics are known.

Transcriptional shift and metabolic adaptations during Leishmania quiescence using stationary-phase and drug pressure as models

Microorganisms can adopt a quiescent physiological condition which acts as a survival strategy under unfavourable conditions. Quiescent cells are characterized by slow or non-proliferation and deep down-regulation of processes related to biosynthesis. Although quiescence has been described mostly in bacteria, this survival skill is widespread, including in eukaryotic microorganisms. In Leishmania, a digenetic parasitic protozoan that causes a major infectious disease, quiescence has been demonstrated, but molecular and metabolic features enabling its maintenance are unknown. Here we quantified the transcriptome and metabolome of Leishmania promastigotes and amastigotes where quiescence was induced in vitro either through drug pressure or by stationary phase. Quiescent cells have a global and coordinated reduction in overall transcription, with levels dropping to as low as 0.4% of those in proliferating cells. However, a subset of transcripts did not follow this trend and were relatively upregulated in quiescent populations, including those encoding membrane components such as amastins and GP63 or processes like autophagy. The metabolome followed a similar trend of overall downregulation albeit to a lesser magnitude than the transcriptome. Noteworthy, among the commonly upregulated metabolites were those involved in carbon sources as an alternative to glucose. This first integrated two omics layers affords novel insights into cell regulation and shows commonly modulated features across stimuli and stages.

Physiological Responses of Two Contrasting Kiwifruit (Actinidia spp.) Rootstocks against Waterlogging Stress

Rootstocks from Actinidia valvata are much more tolerant to waterlogging stress than those from Actinidia deliciosa, which are commonly used in kiwifruit production. To date, the tolerance mechanism of A. valvata rootstocks’ adaptation to waterlogging stress has not been well explored. In this study, the responses of KR5 (A. valvata) and ‘Hayward’ (A. deliciosa) to waterlogging stress were compared. Results showed that KR5 plants performed much better than ‘Hayward’ during waterlogging by exhibiting higher net photosynthetic rates in leaves, more rapid formation of adventitious roots at the base of stems, and less severe damage to the main root system. In addition to morphological adaptations, metabolic responses of roots including sufficient sucrose reserves, modulated adjustment of fermentative enzymes, avoidance of excess lactic acid and ethanol accumulation, and promoted accumulation of total amino acids all possibly rendered KR5 plants more tolerant to waterlogging stress compared to ‘Hayward’ plants. Lysine contents of roots under waterlogging stress were increased in ‘Hayward’ and decreased in KR5 compared with their corresponding controls. Overall, our results revealed the morphological and metabolic adaptations of two kiwifruit rootstocks to waterlogging stress, which may be responsible for their genotypic difference in waterlogging tolerance.

Periodic ethanol supply as a path towards unlimited lifespan of C.elegans dauer larvae

The dauer larva is a specialized stage of development optimized for survival under harsh conditions that has been used as a model for stress resistance, metabolic adaptations, and longevity. Recent findings suggest that the dauer larva of C.elegans may utilize external ethanol as an energy source to extend their lifespan. It was shown that while ethanol may serve as an effectively infinite source of energy, some toxic compounds accumulating as byproducts of its metabolism may lead to the damage of mitochondria and thus limit the lifespan of larvae. A minimal mathematical model was proposed to explain the connection between the lifespan of dauer larva and its ethanol metabolism. To explore theoretically if it is possible to extend even further the lifespan of dauer larvae, we incorporated two natural mechanisms describing the recovery of damaged mitochondria and elimination of toxic compounds, which were previously omitted in the model. Numerical simulations of the revised model suggest that while the ethanol concentration is constant, the lifespan still stays limited. However, if ethanol is supplied periodically, with a suitable frequency and amplitude, the dauer could survive as long as we observe the system. Analytical methods further help to explain how the feeding frequency and amplitude affect the lifespan extension. Based on comparison of the model with experimental data for fixed ethanol concentration, we propose the range of feeding protocols that could lead to even longer dauer survival and can be tested experimentally.

1H HR-MAS NMR Based Metabolic Profiling of Lung Cancer Cells with Induced and De-Induced Cisplatin Resistance to Reveal Metabolic Resistance Adaptations

Cisplatin (cisPt) is an important drug that is used against various cancers, including advanced lung cancer. However, drug resistance is still a major ongoing problem and its investigation is of paramount interest. Here, a high-resolution magic angle spinning (HR-MAS) NMR study is presented deciphering the metabolic profile of non-small cell lung cancer (NSCLC) cells and metabolic adaptations at different levels of induced cisPt-resistance, as well as in their de-induced counterparts (cells cultivated in absence of cisPt). In total, fifty-three metabolites were identified and quantified in the 1H-HR-MAS NMR cell spectra. Metabolic adaptations to cisPt-resistance were detected, which correlated with the degree of resistance. Importantly, de-induced cell lines demonstrated similar metabolic adaptations as the corresponding cisPt-resistant cell lines. Metabolites predominantly changed in cisPt resistant cells and their de-induced counterparts include glutathione and taurine. Characteristic metabolic patterns for cisPt resistance may become relevant as biomarkers in cancer medicine.

Divergent serum metabolomic, skeletal muscle signalling, transcriptomic and performance adaptations to fasted versus whey protein-fed sprint interval training

Sprint interval training (SIT) is a time efficient alternative to endurance exercise, conferring beneficial skeletal muscle metabolic adaptations. Current literature has investigated the nutritional regulation of acute and chronic exercise-induced metabolic adaptations in muscle following endurance exercise, principally comparing the impact of training in fasted and carbohydrate-fed (CHO) conditions. Alternative strategies such as exercising in low CHO, protein-fed conditions remain poorly characterised, specifically pertaining to adaptations associated with SIT. Thus, this study aimed to compare the metabolic and performance adaptations to acute and short term SIT in the fasted state with pre-exercise hydrolysed (WPH) or concentrate (WPC) whey protein supplementation. In healthy males, pre-exercise protein ingestion did not alter exercise-induced increases in PGC-1α, PDK4, SIRT1, and PPAR-δ mRNA expression following acute SIT. However, supplementation of WPC and WPH beneficially altered acute exercise-induced SIRT4 and CD36 mRNA expression, respectively. Pre-exercise protein ingestion attenuated acute exercise-induced increases in muscle pan-acetylation, and PARP1 protein content compared with fasted SIT. Acute serum metabolomic differences confirmed greater pre-exercise amino acid delivery in protein-fed compared with fasted conditions. Following 3 weeks of SIT, training-induced increases in mitochondrial enzymatic activity and exercise performance were similar across nutritional groups. Interestingly, resting muscle acetylation status was favourably regulated in WPH conditions following training. Such findings suggest pre-exercise WPC and WPH ingestion positively influences metabolic adaptations to SIT compared to fasted training, resulting in either similar or enhanced performance adaptations. Future studies investigating nutritional modulation of metabolic adaptations to exercise are warranted to build upon these novel findings.

Endocrine-metabolic Adaptations in Dorper Ewes: Comparison Between Single and Twin Pregnancies During Gestation, Delivery, and Postpartum

The present study involved a blood glucose, hormonal profile, and insulin resistance evaluation in sheep from conception until 48 h postpartum. A total of 60 healthy Dorper ewes, raised under semi-intensive management were included in the study. Two experimental groups were applied: G1, single pregnancy (n = 30) and G2, twin pregnancy (n = 30). The experimental time points were immediately after fixed-time artificial insemination; at 30 d, 90 d, 120 d, 130 d, and 140 d of pregnancy; on the delivery day (DD); and at 24 h (PD1) and 48 h (PD2) postpartum. Blood samples were taken to analyse glucose, insulin, glucagon, cortisol, thyroid hormones (T3 and T4) levels. All parameters showed significant differences over the analysed sample times; however, only cortisol showed differences within groups, with the G1 having higher values than the G2 group. The interaction of the groups in the nine sample times showed a significant result (P = 0.001) only for glucagon. The number of foetuses directly interfered with the glucagon profile throughout gestation and insulin concentration postpartum. The glucose, cortisol, insulin, glucagon, and HOMA IR concentrations increased at DD and decreased at PD1 and PD2. T3 and T4 levels increased at DD. Despite the changes found in the endocrine system and metabolism in Dorper ewes throughout pregnancy, the nutritional management ensured a healthy status during pregnancy, delivery, and postpartum.