APOPTOSIS
·
2022
·Vol. 27
·期 7
·577-589
·
IF 5.561
Ma Liang,Xuan Xiaojing,Fan Minghui,Zhang Yumeng,Yuan Guozan,Huang Guozheng,Liu Zi
Chemotherapy represents one of the main conventional therapies for breast cancer. However, tumor cells develop mechanisms to evade chemotherapeutic-induced apoptosis. Thus, it is of great significance to induce non-apoptotic cell death modes, such as paraptosis, in breast cancer. Herein, a novel 8-hydroxyquinoline derivative, 5,7-dibromo-8-(methoxymethoxy)-2-methylquinoline (HQ-11), was obtained and its potential anti-breast cancer mechanisms were investigated. Our results showed that extensive cytoplasmic vacuoles derived from the endoplasmic reticulum (ER) and mitochondria were appeared in MCF7 and MDA-MB-231 breast cancer cells by HQ-11 incubation, and pretreatment of cycloheximide was able to inhibit this vacuolation and HQ-11-induced cell death, showing the characteristics of paraptosis. ER stress was involved in HQ-11-caused paraptosis evidenced by the increase of glucose-regulated protein 78, C/EBP homologous protein and polyubiquitinated proteins. Molecular docking analysis revealed a favorable binding mode of HQ-11 in the active site of the chymotrypsin-like β5 subunit of the proteasome, indicative of proteasome dysfunction under HQ-11 treatment, which might result in further aggravated ER stress. Furthermore, treatment of HQ-11 resulted in increased phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun NH 2 -terminal kinase, and inhibition of ERK with U0126 significantly attenuated HQ-11-induced ER stress and paraptosis. In addition, exposure to HQ-11 also caused apoptosis in breast cancer cells partially through activation of ERK pathway. All these results conclusively indicate that HQ-11 triggers two distinct cell death modes via inhibition of proteasome and activation of ERK pathway in breast cancer cells, providing a promising candidate in future anti-breast cancer therapy.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Huali Lei,Guanghui Hou,Lin Liu,Zifan Pei,Youdong Chen,Yujie Lu,Nalin Yang,Shumin Sun,Liang Cheng
Iron metabolism has emerged as a promising target for cancer therapy; however, the innate metabolic compensatory capacity of cancer cells significantly limits the effectiveness of iron metabolism therapy. Herein, bioactive gallium sulfide nanodots (GaSx), with dual functions of “reprogramming” and “interfering” iron metabolic pathways, were successfully developed for tumor iron metabolism therapy. The constructed GaSx nanodots ingeniously harness hydrogen sulfide (H2S) gas, which is released in response to the tumor microenvironment, to reprogram the inherent transferrin receptor 1 (TfR1)-ferroportin 1 (FPN1) iron metabolism axis in cancer cells. Concurrently, the gallium ions (Ga3+) derived from GaSx act as a biochemical “Trojan horse”, mimicking the role of iron and displacing it from essential biomolecular binding sites, thereby influencing the fate of cancer cells. By leveraging the dual mechanisms of Ga3+-mediated iron disruption and H2S-facilitated reprogramming of iron metabolic pathways, GaSx prompted the initiation of a paraptosis–apoptosis hybrid pathway in cancer cells, leading to marked suppression of tumor proliferation. Importantly, the dysregulation of iron metabolism induced by GaSx notably increased tumor cell susceptibility to both chemotherapy and immune checkpoint blockade (ICB) therapy. This study underscores the therapeutic promise of gas-based interventions and metal ion interference strategies for the tumor metabolism treatment.
研究领域:
癌症生物学
·
纳米技术
·
药理学
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Zhenhu Guo,Xiaohan Gao,Jingsong Lu,Ying Li,Zeping Jin,Abdul Fahad,Neema Ufurahi Pambe,Hirotaka Ejima,Xiaodan Sun,Xiumei Wang,Wensheng Xie,Guifeng Zhang,Lingyun Zhao
Regarded as one of the hallmarks of tumorigenesis and tumor progression, the evasion of apoptotic cell death would also account for treatment resistance or failure during cancer therapy. In this study, a Ca2+/Cu2+ dual-ion “nano trap” to effectively avoid cell apoptosis evasion by synchronously inducing paraptosis together with apoptosis was successfully designed and fabricated for breast cancer treatment. In brief, disulfiram (DSF)-loaded amorphous calcium carbonate nanoparticles (NPs) were fabricated via a gas diffusion method. Further on, the Cu2+-tannic acid metal phenolic network was embedded onto the NPs surface by self-assembling, followed by mDSPE-PEG/lipid capping to form the DSF-loaded Ca2+/Cu2+ dual-ions “nano trap”. The as-prepared nanotrap would undergo acid-triggered biodegradation upon being endocytosed by tumor cells within the lysosome for Ca2+, Cu2+, and DSF releasing simultaneously. The released Ca2+ could cause mitochondrial calcium overload and lead to hydrogen peroxide (H2O2) overexpression. Meanwhile, Ca2+/reactive oxygen species-associated mitochondrial dysfunction would lead to paraptosis cell death. Most importantly, cell paraptosis could be further induced and strengthened by the toxic dithiocarbamate (DTC)–copper complexes formed by the Cu2+ combined with the DTC, the metabolic products of DSF. Additionally, the released Cu2+ will be reduced by intracellular glutathione to generate Cu+, which can catalyze the H2O2 to produce a toxic hydroxyl radical by a Cu+-mediated Fenton-like reaction for inducing cell apoptosis. Both in vitro cellular assays and in vivo antitumor evaluations confirmed the cancer therapeutic efficiency by the dual ion nano trap. This study can broaden the cognition scope of dual-ion-mediated paraptosis together with apoptosis via a multifunctional nanoplatform.
研究领域:
癌症生物学
·
纳米技术
·
药学
·
细胞生物学
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Youdong Chen,Yujie Lu,Huali Lei,Lin Liu,Xianmin Li,Yuqi Yang,Shumin Sun,Qiao Yu,Li Wang,Jie Wu,Jingrui Li,Guanghui Hou,Liang Cheng
Immunotherapy holds significant promise for cancer treatment. However, the highly immunosuppressive nature of solid tumors limits its effectiveness. Herein, we developed bioactive zinc–nickel hydroxide (ZnNi(OH)4) nanosheets (NSs) that can effectively initiate the paraptosis–pyroptosis positive feedback cycle through synergistic ionic effect, thereby mitigating the immunosuppression of solid tumors and enhancing the efficacy of immunotherapy. The acid-sensitive ZnNi(OH)4 NSs releases Ni2+ and Zn2+ in the weakly acidic tumor microenvironment. The released Ni2+ alleviated pyroptosis inhibition by inducing paraptosis and inhibiting autophagic flux. Concurrently, Ni2+ triggered release of endogenous Zn2+ within the cell through a coordination competition mechanism, further amplifying zinc overload-mediated pyroptosis. Interestingly, pyroptosis-associated oxidative stress and endoplasmic reticulum stress further promote Ni2+-mediated paraptosis, forming a positive feedback loop between pyroptosis and paraptosis. This process not only effectively kills tumor cells but also stimulates a strong inflammatory response, enhancing the antitumor immune response and immunotherapy efficacy. Overall, this study proposes an effective paraptosis–pyroptosis induction strategy based on metal ions and demonstrates the effectiveness of the positive feedback loop of paraptosis–pyroptosis in potentiating immunotherapy.
研究领域:
癌症研究
·
免疫治疗
·
纳米技术
·
细胞生物学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biochemistry and Cell Biology
·
2024
·
IF 2.4
Wei Yan,Ruolan Wu,Yingying Lee,Liqun Xu,Xiao Li,Junwei Li,Ronghao Deng,Xing Fan,Yilang Wu,Haibao Zhu,Aihua Mao,Jianxin Shen,Chi-ju Wei
Enucleated cells, also known as cytoplasts, are valuable tools with a wide range of applications. However, their potential for bio-engineering is greatly restricted by the short lifespan. We postulated that the enucleation process damages the integrity of the plasma membrane and thus activates a cell death program(s). The results showed that a tiny hole was generated transiently on the plasma membrane when the nucleus was spun off, while force-gated ion channels were activated in response to the pulling by the nucleus. Influx of extracellular calcium stimulated the opening of calcium channels and the release of calcium from endoplasmic reticulum and mitochondria. Long lasting calcium transient increased protein phosphorylation and activated caspase 9 and calpain proteinase activities. Subsequently, mitochondria membrane permeability and Reactive Oxygen Species (ROS) levels were significantly elevated, which eventually led to eryptosis-like cell death. When extracellular calcium was maintained at optimal concentration, the lifespan of enucleated cells was extended; however, huge amounts of vacuoles appeared in the cytoplasm, possibly derived from enlarged autophagosomes. Inhibition of vacuolation by inhibitors of autophagy or in co-culture with primary muscle cells did not rescue cells dying from the paraptosis-like pathway. These results offer valuable insights for further investigation into the intricate mechanisms underlying enucleated cell death.
研究领域:
细胞生物学
·
干细胞研究
·
分子生物学
·
钙信号传导
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）