Cell Death and Differentiation最新文献

The mechanistic target of rapamycin complex 2 (mTORC2) signaling pathway, which regulates cell growth and migration, exhibits oncogenic function in colorectal cancer (CRC). mTORC2 signaling is primarily activated by a complex assembly of mTOR, RICTOR, SIN1, and mLST8; however, the mechanisms by which dysregulation of this pathway contributes to its oncogenic function remain elusive. Here, we show that the Src-Like Adaptor Protein (SLAP), a negative regulator of tyrosine kinase signaling receptors, controls mTORC2 integrity to mediate its tumor-suppressive function in CRC. Mechanistically, SLAP interacts with mLST8 and facilitates its non-degradative ubiquitination at lysines 86 and 215, thereby reducing the integrity of mTORC2 and mTORC2-AKT signaling. The E3 ubiquitin ligase UBE3C was identified as a novel SLAP interactor involved in this ubiquitination process. Functionally, SLAP inhibition of CRC cell growth and invasion was dependent upon mTORC2 signaling inhibition. In immunodeficient mice CRC xenografts, SLAP depletion enhanced mTORC2 activity and sensitized CRC cells to mTOR catalytic inhibitors. Together, our findings reveal a previously unrecognized SLAP-UBE3C-mLST8 axis that regulates mTORC2 integrity and suggest a potential therapeutic avenue for targeting mTORC2 in CRC.

Recent FDA approval for treating Alzheimer's disease (AD) with amyloid-beta (Aβ) immunotherapy is a historic breakthrough, which has rekindled widespread interest in understanding the molecular basis of Aβ toxicity. In this study, we developed a novel Drosophila model to investigate Aβ42-induced pathologies in vivo and in real time. Strikingly, we unveiled compelling evidence that secreted Aβ42 affects different neurons in distinct ways-both in susceptibility to Aβ42 deposition and in the mode of cell death triggered. Additionally, we observed altered larval crawling behaviour which-remarkably-could be recovered by inhibiting ferroptotic cell death with small molecule inhibitors. Collectively these findings showcase this as a powerful new model for investigating Aβ toxicity in AD and identifying novel treatment strategies.

Parkinson's disease (PD) is characterized by the aggregation of misfolded α-synuclein (α-syn) and microglial activation. Galectin-9 (Gal-9) is an immunoregulatory mediator generated by microglia. Here, we found that α-syn fibrils are internalized by microglia and processed by microglial protease AEP, generating α-syn species with enhanced seeding activity and neurotoxicity. Notably, the uptake of α-syn fibrils by microglia leads to increased expression of Gal-9, which further promotes the production of toxic α-syn species via activation of the C/EBPβ/AEP axis. Knockout of Gal-9 attenuates α-syn pathology, dopaminergic neuronal loss, and motor impairments in a mouse model induced by intrastriatal injection of α-syn PFFs. Intrastriatal injection of Gal-9 promoted PD-like phenotypes induced by α-syn PFFs. Furthermore, the detrimental effect of Gal-9 was attenuated by the knockout of AEP. These observations illustrate the key role of Gal-9 in promoting α-syn pathology and neurodegeneration via the C/EBPβ/AEP axis in PD.

Fatty acid metabolism is critical for tumor progression, supplying bioenergetic and biosynthetic substrates to rapidly proliferating cancer cells. However, the precise mechanisms by which fatty acid metabolism influences breast cancer progression remain unclear. In this study, we aimed to explore the molecular mechanism by which C-Jun activation domain-binding protein-1 (JAB1) promotes breast cancer progression through regulating fatty acid metabolism. The JAB1 is identified as an oncogene in breast cancer. JAB1 promotes cell proliferation, invasion, and stemness by stabilizing CUL4B protein. Mechanistically, JAB1 forms a transcriptional repressor complex with the Cullin 4B-Ring E3 ligase (CRL4B) complex, co-occupying the promoters of key fatty acid metabolism genes, PPARG and ACSL5, thus leading to their transcriptional repression. This activates fatty acid metabolism, increasing mitochondrial oxygen consumption and supporting the energetic demands of tumor cells. Notably, JAB1 inhibition reverses chemotherapy resistance associated with CUL4B overexpression. These findings underscore the pivotal role of JAB1 in regulating breast cancer progression and indicate that JAB1 inhibitors could serve as promising therapeutics for patients with elevated CUL4B expression.

Death ligands, including FAS ligand (FASL) and tumor necrosis factor (TNF), trigger apoptosis by promoting caspase-8 dimerization and activation. Impaired FAS signaling causes unconventional lymphocytes to accumulate, resulting in lymphadenopathy. Although autoprocessing of caspase-8 is considered important for apoptosis, autoprocessing-deficient Casp8^D387A/D387A mice do not develop lymphadenopathy. We show that this is because heterodimers of caspase-8 D387A and cFLIP, besides suppressing MLKL-driven necroptosis, can also induce apoptosis. Interestingly, caspase-8 D387A elicited MLKL- and caspase-1-independent intestinal atrophy and perinatal lethality in mice lacking cFLIP. Caspase-8 D387A interacted with FADD and RIPK1 in the intestine, where there was aberrant cleavage of N4BP1 and caspase-3, plus enhanced NF-κB signaling. Eliminating FADD, the adaptor protein that promotes caspase-8 oligomerization, prevented this perinatal lethality. Collectively, our results suggest that cFLIP forms heterodimers with caspase-8 D387A to promote apoptosis in some contexts, while limiting the activity of caspase-8 D387A homodimers in others.

Chemotherapy is essential for cancer management yet frequently accompanied with adverse effects, particularly for temozolomide (TMZ), a frontline chemotherapeutic agent for glioma. Although clinical neurological abnormalities linked to TMZ have been observed, mechanisms underlying TMZ-induced neural impairments remain poorly understood, and effective interventions are lacking. Here, we demonstrated that TMZ chemotherapy induced neurodegenerations that recapitulated pathological features of multiple sclerosis, including demyelination, neuroinflammation and axonal degeneration. In adolescent mice, TMZ treatment resulted in severe white matter damage that spontaneously recovered, whereas in adult mice, moderate myelin damage persisted without recovery within the same timeframe. Importantly, we identified that clobetasol effectively reversed TMZ-induced white matter damage and trends toward anxiety and depression in adult mice by suppressing TMZ-induced AMPK activation and attenuating neuroinflammation, thereby promoting remyelination. Our findings reveal the previously underappreciated neural toxicities associated with TMZ chemotherapy and highlight the therapeutic efficacy of clobetasol in mitigating chemotherapy-induced neural impairment, providing a strategy to enhance the life quality of cancer patients.

The lymph node is the most common site of distant metastasis of cervical cancer (CCa), which elicits dismal prognosis and limited efficiency for treatment. Identification of the factors contributing to CCa lymphatic metastasis is needed to develop effective prevention and treatment strategies. Here, we found upregulation of prolyl 4-hydroxylase subunit alpha 3 (P4HA3), an α-subunit of prolyl hydroxylase, in lymphatic metastatic lesions of cervical cancer, which is strongly associated with poor prognosis. In vitro and in vivo experiments showed that P4HA3 promoted CCa lymphatic metastasis by conferring ATP-citrate lyase (ACLY)-mediated ferroptosis resistance. Mechanistically, P4HA3 stabilizes ACLY protein by competitively inhibiting its interaction with the E3 ubiquitin ligase UBR4, which prevents UBR4-mediated proteasomal degradation of ACLY. ACLY-derived acetyl-CoA enhances H3K27 acetylation (H3K27ac) modification level in the promoter of SLC7A11 gene, ultimately enhancing SLC7A11 transcription and ferroptosis resistance. Collectively, our study provides a mechanistic understanding of the interplay between ferroptosis resistance and lymph node metastasis, providing a possibility to combat lymph node metastasis in cervical cancer.