Cell Death & Disease最新文献

Prostate cancer (PCa) is the most prevalent malignancy among men worldwide. Advanced prostate cancer is characterized by aggressive progression, limited therapeutic response, and poor prognosis. Elucidating its oncogenic mechanisms may provide new opportunities for targeted intervention. Increasing evidence suggests that modulating cytoprotective autophagy represents a promising strategy for improving cancer treatment efficacy and overcoming drug resistance. Here, we identified the G protein subunit GNG4 as a crucial regulator of prostate cancer development. GNG4 expression was markedly elevated in advanced prostate cancer phenotypes and positively correlated with tumor survival, apoptosis, and migration. Further analysis demonstrated that GNG4 depletion suppressed autophagy and enhanced cellular sensitivity to enzalutamide. Mechanistically, GNG4 interacts with GNB1 to stabilize the downstream effector protein GNAI3 through the ubiquitination-proteasome pathway. These three distinct G protein subunits form a functional complex that regulates intracellular autophagy and subsequently influences the malignant behavior of prostate cancer. Furthermore, inhibition of autophagy or GNG4 knockdown significantly increased the antitumor efficacy of enzalutamide both in vitro and in vivo. Our findings identified GNG4 as a pivotal modulator of prostate cancer progression and proposed it as a promising therapeutic target to enhance the clinical response to enzalutamide. GNG4 interacts with GNB1 to stabilize GNAI3 via the ubiquitination-proteasome pathway, thereby activating autophagy. This process promotes prostate cancer progression and resistance to androgen receptor signaling inhibitors (ARSis). In contrast, GNG4 knockdown or pharmacological inhibition of autophagy restores ARSI sensitivity and suppresses tumor growth.

Colorectal Cancer (CRC) progression is a complex and dynamic process closely linked to TET2-mediated DNA demethylation. Distinct from our previous study on TET2 nuclear loss, which can be observed in the whole tumor progression process, the nuclear increase of TET2 was only observed in tumors at the beginning of metastasis. In addition, cells with nuclear TET2 were located at the bottom of the mucosa, which is the invasion front of CRC. All of these results suggested crucial roles of TET2 nuclear increase during tumor progression. Mechanistically, epithelial-mesenchymal transition (EMT) and the activation of the WNT pathway, which is normally recognized as tumor promotion events, were shown to correlate with the cytoplasm-nucleus shuttling of TET2, which is associated with tumor suppression. Nuclear TET2, in turn, mitigated further EMT and WNT activation, suggesting a negative feedback loop between TET2 and the EMT/WNT pathway. Such a negative feedback loop was further supported by single-cell RNA sequencing (scRNA-seq) analysis of both the CRC progression models and the clinical CRC samples. Together, these findings indicate that the tumor inhibition role of EMT/WNT pathway and TET2 is an intrinsic brake on cancer progression, which represents a potential therapeutic target for CRC.

Sec8, an exocyst complex subunit, is pivotal in facilitating the docking of exocytic vesicles to fusion sites on the plasma membrane. However, its involvement in the antiviral innate immune response and virus replication remains unclear. In this study, Sec8 is identified as a novel positive regulator of RIG-I, enhancing the IFN-I signaling response against RNA viruses both in vivo and in vitro. Additionally, Sec8 stabilizes RIG-I by inhibiting its ubiquitination and subsequent proteasome-mediated degradation. Mechanistically, STUB1 degrades RIG-I via K48-linked ubiquitination at Lys190, while Sec8 suppresses STUB1 mRNA by reducing the expression of p53 and competes with STUB1 for binding to RIG-I's CARD domain, thereby preventing STUB1-mediated RIG-I degradation. Importantly, Sec8-deficient mice were more susceptible to RNA virus infection compared to wild-type mice. These findings elucidate a mechanism that Sec8 positively regulates RIG-I in the antiviral innate immune response, offering insights for developing novel therapeutic strategies and targeted antiviral medications.

Antibody-drug conjugates (ADC) offer a targeted cancer treatment approach by delivering cytotoxic payloads directly to tumor cells. However, resistance mechanisms, poor tumor penetration, and off-target toxicity often limit clinical efficacy. Vartumab targets oncofetal chondroitin sulfate (ofCS), a pan-cancer target present on tumor cells and in the malignant stroma, with low expression in normal tissues. As part of transitioning Vartumab to clinical evaluation, two linker-payloads known to mediate bystander effects, valine-citrulline (vc)-monomethyl auristatin E (MMAE) and glycine-glycine-phenylalanine-glycine (ggfg)-Deruxtecan (DXd), were investigated for design of Vartumab ADCs. We show that the ADCs maintain specificity to ofCS proteoglycans, cancer cells, and tissue biopsies, exhibiting specific binding to a wide range of malignant and metastatic tissues. Biodistribution assessment of Vartumab ADCs in mice shows strong and specific tumor uptake, with minimal accumulation in other organs. Both ADCs induced bystander killing of antigen-negative cells in the presence of antigen-positive cells and displayed potent anti-tumor activities in a cell-derived xenograft melanoma model. Furthermore, we show that Vartumab conjugates with bystander-capable linker-payloads exhibit greater in vivo potency compared to those with payloads lacking significant bystander effect. Finally, toxicity assessment in rats indicates that the ADC-MMAE is well-tolerated upon repeated doses, with similar dose-limiting toxicities as reported for clinically approved MMAE-conjugated ADCs. Our data support further clinical development of Vartumab-based ADCs.

Clear cell renal cell carcinoma (ccRCC) is characterized by disrupted lipid metabolism, traditionally attributed to VHL mutations and HIF stabilization. Here, we identified CEBPB as an epigenetically upregulated, VHL-independent transcription factor driving ccRCC tumorigenesis. CEBPB was regulated by H3K27ac and H3K4me and transcriptionally repressed the tumor-suppressive glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L), thereby elevating dihydroxyacetone phosphate (DHAP)-derived ether lipid synthesis and enhancing Akt signaling. This activation suppressed CPT1A expression, inhibiting fatty acid oxidation (FAO) and leading to lipid accumulation, as found by lipidomics and isotope tracing. Loss of CEBPB reduced ether lipids, reactivated CPT1A, and impaired Akt signaling, diminishing tumor growth and lipid content in vitro and in vivo. Restoration of ether lipids or Akt activity rescued these effects. Importantly, CEBPB expression and enhancer activation were not modulated by VHL status and it could be targeted pharmacologically. The CEBPB-GPD1L-ether lipid-Akt-CPT1A axis is proposed as a new druggable driver in ccRCC integrating epigenetics, transcription, intermediary metabolism and oncogenic signaling.

Lactate, a key byproduct of glycolysis in tumor cells, has emerged as more than just a metabolic waste product. Increasing evidence reveals that lactate and its associated post-translational modification (PTM), lactylation, play multifaceted roles in regulating various forms of regulated cell death (RCD), thereby contributing to cancer proliferation, therapy resistance, and immune exclusion. Notably, evasion of RCD is a hallmark of cancer and targeting RCD may represent a promising therapeutic strategy for cancer treatment. In this review, we focus on summarizing the dual and context-dependent roles of both lactate and lactylation in modulating distinct types of RCD, including apoptosis, autophagy, ferroptosis, pyroptosis, and cuproptosis. Moreover, we further discuss how RCD processes impact lactate metabolism and highlight the therapeutic potential and current challenges of targeting the lactate-lactylation-RCD axis in cancer treatment.