Selected Articles from This Issue

Tumor aggressiveness is closely linked to the metabolic adaptations of cancer cells, and uncovering the mechanisms behind these changes can reveal therapeutic vulnerabilities. In their study, Joshi and colleagues uncover a TRAP1-dependent mechanism that conserves glutamine through regulation of the cystine/glutamate antiporter SLC7A11/xCT. Using oxygen consumption rate assays, the authors showed that TRAP1 knockout cells have significantly higher mitochondrial respiration when glutamine is the sole carbon source, but reduced respiration when supplied only with glucose. Stable isotope tracing with uniformly labeled 13C-glucose demonstrated that, although glucose oxidation remains functional, TRAP1 knockout cells exhibit reduced glucose uptake and decreased contribution of glucose-derived carbons to both glycolysis and the pentose phosphate pathway. Complementary 13C-glutamine tracing reveals an anaplerotic shift in TRAP1-deficient cells, with glutamine fueling both the oxidative arm of the tricarboxylic acid cycle and reductive carboxylation. The study further shows that glutamine retention in TRAP1 knockout cells is associated with decreased xCT protein levels, limiting glutamate export. This xCT downregulation occurs without triggering ferroptosis and is regulated post-translationally through proteasome-dependent degradation, likely by a ubiquitin-independent mechanism. Restoring xCT expression in TRAP1 knockout cells reduces glutamine-dependent respiration to wild-type–like levels. Taken together, these findings reveal a TRAP1-linked metabolic rewiring strategy in which reduced glucose use is balanced by conserved glutamine utilization, highlighting TRAP1 as a potential therapeutic target in tumors with altered nutrient dependencies.HER2+ breast cancer is a highly aggressive metastatic form of breast cancer that commonly recurs despite treatment with HER2-targeted therapies. To improve treatment outcomes, Manupati and colleagues screened alternative metastasis-associated protein targets and identified PI3KC2β as a potential metastatic suppressor. Mice orthotopically injected with PI3KC2β knockout HER2+ breast cancer cells had a significant increase in metastatic nodules in the lung compared to the control. Subsequent tail vein injection models and in vitro trans-well assays for PI3KC2β knockout cells also supported a potential antimetastatic role of PI3KC2β. Analysis of TCGA data and immunohistochemical staining of human breast cancer tissues further demonstrated that low expression of PI3KC2β was associated with poorer survival and that PI3KC2β expression was lower in metastatic tissue compared to the primary tumor. The authors also evaluated the impact of PI3KC2β on mTORC1 signaling, finding murine PI3KC2β knockout and human PI3KC2β knockdown tumor cells contained higher levels of phosphorylated S6K. PI3KC2β knockout cells treated with an AKT inhibitor highlighted the AKT-dependent nature of this mTORC1 activation. Kinase inactive mutant PI3KC2β cell models established that PI3KC2β-restrained mTOR1 signaling is a lipid kinase independent mechanism. PI3KC2β binding partners were identified using coimmunoprecipitation and confocal microscopy, and a PI3KC2β/Raptor/ITSN1 complex was found to regulate mTORC1 signaling through the complex-mediated degradation of raptor. Altogether these findings identify a PI3KC2β-mediated metastatic suppression mechanism and highlight it as a potential therapeutic target against HER2+ breast cancer metastasis.Irradiation, while a useful therapeutic tool for many types of cancer, can also cause significant damage to healthy patient tissues. Enhanced understanding of radioprotective mechanisms may reveal novel targets to decrease collateral irradiation-induced damage. To address this, Affandi and colleagues investigated the mechanism of PKCδ-mediated radiosensitivity. Measurement of cellular ROS, mitochondrial ROS, and superoxide revealed enhanced levels of these species in PKCδ knockdown cells compared to the control. Comet assays further demonstrated that these ROS may primarily function as signaling molecules to activate antioxidant responses, as increased levels of ROS in PKCδ. knockdown cells did not correspond to increased levels of DNA damage. Mitochondrial dyes and Seahorse Mito Stress Tests showed that the elevated ROS production in PKCδ-depleted cells can be attributed to the dysregulation of Complex I and III in the electron transport chain. Enzymatic assays and metabolite analysis further showed that PKCδ-depleted cells produced increased levels of glutathione, sustained by upregulation of the glutathione synthesis pathway and inhibition of its consumption. Mechanistic studies found that PKCδ depletion enhances the antioxidant response through activation of a SIRT6/Nrf2 pathway. Overall, this study indicates that PKCδ mediates mitochondrial function and ROS production in a SIRT6/Nrf2-dependent manner, which may be clinically modulated to improve radioprotection.