PARP inhibitors (PARPi) have drastically changed the treatment landscape of advanced ovarian tumors with BRCA mutations. However, the impact of this class of inhibitors in patients with advanced ...BRCA-mutant breast cancer is relatively modest. Using a syngeneic genetically-engineered mouse model of breast tumor driven by Brca1 deficiency, we show that tumor-associated macrophages (TAMs) blunt PARPi efficacy both in vivo and in vitro. Mechanistically, BRCA1-deficient breast tumor cells induce pro-tumor polarization of TAMs, which in turn suppress PARPi-elicited DNA damage in tumor cells, leading to reduced production of dsDNA fragments and synthetic lethality, hence impairing STING-dependent anti-tumor immunity. STING agonists reprogram M2-like pro-tumor macrophages into an M1-like anti-tumor state in a macrophage STING-dependent manner. Systemic administration of a STING agonist breaches multiple layers of tumor cell-mediated suppression of immune cells, and synergizes with PARPi to suppress tumor growth. The therapeutic benefits of this combination require host STING and are mediated by a type I IFN response and CD8
T cells, but do not rely on tumor cell-intrinsic STING. Our data illustrate the importance of targeting innate immune suppression to facilitate PARPi-mediated engagement of anti-tumor immunity in breast cancer.
Metabolic reprogramming is fundamental to biological homeostasis, enabling cells to adjust metabolic routes after sensing altered availability of fuels and growth factors. ULK1 and ULK2 represent key ...integrators that relay metabolic stress signals to the autophagy machinery. Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1). Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels. These results identify ULK1/2 as a bifurcate-signaling node that sustains glucose metabolic fluxes besides initiation of autophagy in response to nutritional deprivation.
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•ULK1/2 deficiency leads to reduction of glycolysis during nutritional stresses•HK1, PFK1, FBP1, and ENO1 are direct substrates of the ULK1 kinase•ULK1 regulates activities of glycolytic enzymes and sustains glycolysis and PPP flux•ULK1/2 reprogram glucose metabolic fluxes independently of autophagy
Metabolic reprogramming underlies adaptive responses to various stresses. Li et al. discover that the autophagy-initiating kinases ULK1/2 also phosphorylate multiple glycolytic enzymes to sustain glycolysis and increase the proportion of glucose flux to the pentose phosphate pathway during nutritional stresses.
Prostate cancer (PCa) is an extensive heterogeneous disease with a complex cellular ecosystem in the tumor microenvironment (TME). However, the manner in which heterogeneity is shaped by tumors and ...stromal cells, or vice versa, remains poorly understood. In this study, single‐cell RNA sequencing, spatial transcriptomics, and bulk ATAC‐sequence are integrated from a series of patients with PCa and healthy controls. A stemness subset of club cells marked with SOX9highARlow expression is identified, which is markedly enriched after neoadjuvant androgen‐deprivation therapy (ADT). Furthermore, a subset of CD8+CXCR6+ T cells that function as effector T cells is markedly reduced in patients with malignant PCa. For spatial transcriptome analysis, machine learning and computational intelligence are comprehensively utilized to identify the cellular diversity of prostate cancer cells and cell‐cell communication in situ. Macrophage and neutrophil state transitions along the trajectory of cancer progression are also examined. Finally, the immunosuppressive microenvironment in advanced PCa is found to be associated with the infiltration of regulatory T cells (Tregs), potentially induced by an FAP+ fibroblast subset. In summary, the cellular heterogeneity is delineated in the stage‐specific PCa microenvironment at single‐cell resolution, uncovering their reciprocal crosstalk with disease progression, which can be helpful in promoting PCa diagnosis and therapy.
Understanding the cellular heterogeneity within the prostate cancer (PCa) microenvironment is crucial for unraveling the mechanisms that drive tumor progression. Bian et al. integrate single‐cell RNA sequencing, spatial transcriptomics, and bulk ATAC‐sequence analysis to provide a multi‐dimensional view of the complex ecosystem in the tumor microenvironment. Findings from this research can provide novel perspectives when treating advanced prostate cancer.
Elucidating the tumorigenic mechanism of R-2-hydroxyglutarate (R-2HG) is critical for determining how NADP+-IDH mutations cause cancer. Here we report that R-2HG induces cancerous metabolism and ...apoptosis resistance through promoting hypersuccinylation. By competitive inhibition of the mitochondrial tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH), R-2HG preferentially induced succinyl-CoA accumulation and hypersuccinylation in the mitochondria. IDH1 mutation-bearing glioma samples and cells were hypersuccinylated in the mitochondria. IDH1 mutation or SDH inactivation resulted in hypersuccinylation, causing respiration inhibition and inducing cancerous metabolism and mitochondrial depolarization. These mitochondrial dysfunctions induced BCL-2 accumulation at the mitochondrial membrane, leading to apoptosis resistance of hypersuccinylated cells. Relief of hypersuccinylation by overexpressing the desuccinylase SIRT5 or supplementing glycine rescued mitochondrial dysfunctions, reversed BCL-2 accumulation, and slowed the oncogenic growth of hypersuccinylated IDH1R132C-harboring HT1080 cells. Thus, R-2HG-induced hypersuccinylation contributes to the tumorigenicity of NADP+-IDH mutations, suggesting the potential of hypersuccinylation inhibition as an intervention for hypersuccinylation-related tumors.
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•R-2HG competitively inhibits SDH and induces hypersuccinylation•IDH1 mutations preferentially induce hypersuccinylation in mitochondria•Hypersuccinylation impairs mitochondrial functions and induces apoptosis resistance•Relief of hypersuccinylation inhibits oncogenic growth of hypersuccinylated cells
NADP+-IDH mutation-produced R-2-hydroxyglutarate induces mitochondrial hypersuccinylation that induces cancerous metabolism and apoptosis resistance. Relief of hypersuccinylation inhibits tumorigenic growth of IDH mutant-harboring cells. Thus, hypersuccinylation contributes to oncogenicity of R-2-hydroxyglutarate.
Lactate is abundant in rapidly dividing cells owing to the requirement for elevated glucose catabolism to support proliferation
. However, it is not known whether accumulated lactate affects the ...proliferative state. Here we use a systematic approach to determine lactate-dependent regulation of proteins across the human proteome. From these data, we identify a mechanism of cell cycle regulation whereby accumulated lactate remodels the anaphase promoting complex (APC/C). Remodelling of APC/C in this way is caused by direct inhibition of the SUMO protease SENP1 by lactate. We find that accumulated lactate binds and inhibits SENP1 by forming a complex with zinc in the SENP1 active site. SENP1 inhibition by lactate stabilizes SUMOylation of two residues on APC4, which drives UBE2C binding to APC/C. This direct regulation of APC/C by lactate stimulates timed degradation of cell cycle proteins, and efficient mitotic exit in proliferative human cells. This mechanism is initiated upon mitotic entry when lactate abundance reaches its apex. In this way, accumulation of lactate communicates the consequences of a nutrient-replete growth phase to stimulate timed opening of APC/C, cell division and proliferation. Conversely, persistent accumulation of lactate drives aberrant APC/C remodelling and can overcome anti-mitotic pharmacology via mitotic slippage. In sum, we define a biochemical mechanism through which lactate directly regulates protein function to control the cell cycle and proliferation.
Oxidative phosphorylation (OXPHOS) consumes oxygen to produce ATP. However, the mechanism that balances OXPHOS activity and intracellular oxygen availability remains elusive. Here, we report that ...mitochondrial protein lactylation is induced by intracellular hypoxia to constrain OXPHOS. We show that mitochondrial alanyl-tRNA synthetase (AARS2) is a protein lysine lactyltransferase, whose proteasomal degradation is enhanced by proline 377 hydroxylation catalyzed by the oxygen-sensing hydroxylase PHD2. Hypoxia induces AARS2 accumulation to lactylate PDHA1 lysine 336 in the pyruvate dehydrogenase complex and carnitine palmitoyltransferase 2 (CPT2) lysine 457/8, inactivating both enzymes and inhibiting OXPHOS by limiting acetyl-CoA influx from pyruvate and fatty acid oxidation, respectively. PDHA1 and CPT2 lactylation can be reversed by SIRT3 to activate OXPHOS. In mouse muscle cells, lactylation is induced by lactate oxidation-induced intracellular hypoxia during exercise to constrain high-intensity endurance running exhaustion time, which can be increased or decreased by decreasing or increasing lactylation levels, respectively. Our results reveal that mitochondrial protein lactylation integrates intracellular hypoxia and lactate signals to regulate OXPHOS.
With the continuous development of society, people are paying more attention to sports. In order to make sports brands go to the international market, it is necessary to adopt an international ...marketing strategy for sports brands. However, due to the late development of most sports brands, the main sports brand market is the mid-to-low-end market. Sports brands have little investment in scientific research and technology and build the market with celebrity endorsements or ultra-low prices. This leads to the lack of an international market for most sports brands, and the sports brands cannot be fully developed. Sports equipment is the core of sports brand marketing, and better quality sports equipment can affect the marketing strategy of sports brands, which improves their international sales capability. High-performance composite sports equipment has many advantages. Compared with traditional sports materials, it has high tensile strength, high wear resistance, and high corrosion resistance. High-performance composite materials were applied to sports equipment and were compared with traditional sports equipment. The quality of the sports equipment, the promotion of the sports brand, the positioning of the sports brand, and the sponsorship of the sports brand were compared between the two sports equipment brands. The test results showed that high-performance composite sports equipment could improve the quality of sports equipment by 25% and had greatly improved sports brand promotion, sports brand positioning, and sports brand sponsorship. Therefore, high-performance composite sports equipment can improve the marketing ability of sports brands in the international market by affecting the quality of sports equipment, promotion of sports brands, positioning of sports brands, and sponsorship of sports brands.
PurposeThe main purpose of this study is to investigate the effects of flexibility-oriented human resource management (FHRM) systems on intellectual capital and organizational resilience. This study ...also examines the moderating effect of digital capability on the relationship between intellectual capital and organizational resilience.Design/methodology/approachData were collected from 219 Chinese businesses in the Yangtze River Delta region of China during the COVID-19 pandemic. Confirmatory factor analysis was used to verify the validity and reliability of the measurements, and hypotheses were tested using hierarchical regression.FindingsThe empirical results show that FHRM systems are positively correlated with intellectual capital and organizational resilience. Intellectual capital mediates the link between FHRM systems and organizational resilience. Moreover, digital capability serves as a positive moderator between intellectual capital and organizational resilience.Originality/valueFrom the perspectives of resilience theory, the resource-based view and the theory of dynamic capabilities, this study is among the first to identify the process mechanism by which FHRM systems affect organizational resilience through intellectual capital. Digital capability is introduced as a situational factor for understanding the effect of intellectual capital on organizational resilience, which provides new insights for further research.
Despite the fact that dockless bike-sharing (DBS) usage first experienced explosive growth, its continuous usage rate remains low. The ultimate success of a DBS service is more dependent on its ...continued usage rather than its initial adoption. Following the extended technology acceptance model (TAM), this study aims to explore factors that influence the continuance intention of DBS users. The framework of research was validated using a sample of 369 DBS users in China. The results show that perceived usefulness and perceived ease of use positively influence a user's intention to continue using DBS. Both descriptive social norms and injunctive social norms are positively related to the continuance intention of DBS users. Moreover, environmental concern significantly affects the continuance intention of a user indirectly
perceived usefulness and perceived ease of use. Furthermore, the extended TAM has stronger prediction ability than the original TAM in the context of DBS services.
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