Engaging in exercise while undergoing radiotherapy (RT) has been reported to be safe and achievable. The impact of exercise training (ET) on RT efficiency is however largely unknown. Our study aims to investigate the interactions between ET and RT on prostate cancer growth. Athymic mice received a subcutaneous injection of PPC‐1 cells and were randomly assigned to either cancer control, cancer ET, cancer RT, or cancer RT combined with ET (CaRT‐ET). Mice were sacrificed 24 days post‐injection. All three intervention groups had reduced tumor size, the most important decrease being observed in CaRT‐ET mice. Apoptotic marker cleaved caspase‐3 was not modified by ET, but enhanced with RT. Importantly, this increase was the highest when the two strategies were combined. Furthermore, NK1.1 staining and gene expression of natural killer (NK) cell receptors Klrk1 and Il2rβ were not affected by ET alone but were increased with RT, this effect being potentiated when combined with ET. Overall, our study shows that (a) ET enhances RT efficiency by potentiating NK cell infiltration, and (b) while ET alone and ET combined with RT both reduce tumor growth, the mechanisms mediating these effects are different.

Autophagy plays a complex role in several cancer types, including endocrine-dependent cancers, by fueling cellular metabolism and clearing damaged substrates. This conserved recycling process has a dual function across tumor types where it can be tumor suppressive at early stages but tumor promotional in established disease. This review highlights the controversial roles of autophagy in endocrine-dependent tumors regarding cancer initiation, tumorigenesis, metastasis, and treatment response. We summarize clinical trial results thus far and highlight the need for additional mechanistic, preclinical, and clinical studies in endocrine-dependent tumors, particularly in breast cancer and prostate cancer.

Physical activity is increasingly recognized as a strategy able to improve cancer patient outcome, and its potential to enhance treatment response is promising, despite being unclear. In our study we used a preclinical model of prostate cancer to investigate whether voluntary wheel running (VWR) could improve tumor perfusion and enhance radiotherapy (RT) efficiency. Nude athymic mice were injected with PC-3 cancer cells and either remained inactive or were housed with running wheels. Apparent microbubble transport was enhanced with VWR, which we hypothesized could improve the RT response. When repeating the experiments and adding RT, however, we observed that VWR did not influence RT efficiency. These findings contrasted with previous results and prompted us to evaluate if the lack of effects observed on tumor growth could be attributable to the physical activity modality used. Using PC-3 and PPC-1 xenografts, we randomized mice to either inactive controls, VWR, or treadmill running (TR). In both models, TR (but not VWR) slowed down tumor growth, suggesting that the anti-cancer effects of physical activity are dependent on its modalities. Providing a better understanding of which activity type should be recommended to cancer patients thus appears essential to improve treatment outcomes.

Le cancer de la prostate est un fléau mondial et l’échec des traitements est un défi majeur pour combattre cette maladie. La pratique d’une activité physique chez des patients atteints d’un cancer est associée à une amélioration du pronostic et certains mécanismes biologiques sous-jacents à ces bénéfices ont été identifiés grâce à des modèles précliniques. Il est dès lors plausible que l’activité physique améliore l’efficacité des traitements utilisés contre le cancer. Toutefois, l’effet de l’activité physique sur l’efficacité de la radiothérapie reste méconnu. L’objectif a cette thèse est d’étudier l’impact de l’activité physique sur la croissance tumorale et la réponse à la radiothérapie dans différents modèles précliniques de cancer de la prostate. Notre travail montre (1) qu’un entrainement sur tapis roulant permet d’améliorer l’efficacité de la radiothérapie dans un modèle préclinique de cancer de la prostate PPC-1 en améliorant l’infiltration des cellules tueuses naturelles dans le tissu tumoral ; (2) qu’un modèle de roue volontaire ne permet pas d’obtenir ces effets chez des souris porteuses de tumeurs PC-3, ce qui semble être attribuable au sous-type de cancer plutôt qu’à la modalité d’activité physique ; et (3) que les processus épigénétiques au sein de la tumeur sont régulés par l’activité physique chez des rats porteurs de tumeurs AT1, le rôle de cet effet sur l’efficacité des traitements restant à explorer. Nos travaux suggèrent donc que l’activité physique pourrait sensibiliser les cellules cancéreuses prostatiques à la radiothérapie et souligne également la nécessité de programmes d’entrainement personnalisés pour les patients atteints de cancer pourrait améliorer l’efficacité de la radiothérapie.

Mitohormesis, whereby transient mitochondrial stress induces adaptive signaling, promotes organismal resilience and longevity in invertebrates, but how this operates in mammals and the underlying metabolic signals involved remain unclear. Using a mouse model of mitohormesis, we show that transient mitochondrial superoxide stress during embryogenesis reprograms the adult heart to enhance mitochondrial biogenesis and antioxidant capacity. These adaptations confer protection against mitochondrial and oxidative injury in models of doxorubicin-induced cardiotoxicity, preserving mitochondrial content and preventing cardiac dysfunction and remodeling. Using a cell model of superoxide-mediated mitohormesis, we find that inhibition of mitochondrial aconitase promotes citrate export to the cytosol, where its conversion to acetyl–coenzyme A drives histone acetylation and mitohormetic protection from oxidative stress. Preventing mitochondrial citrate export abolishes these adaptations, while Aco2 silencing or citrate supplementation recapitulates the response. Together, our findings identify mitochondrial citrate as a redox-sensitive second messenger linking mitochondrial superoxide stress to durable epigenetic and mitohormetic remodeling.