International Journal of Biological Sciences
·
2024
·Vol. 20
·期 2
·516-536
·
IF 8.2
Tian Shaoping,Wang Rui,Wang Yiting,Chen Ruibing,Lin Tianyu,Xiao Xuesong,Liu Xinyu,Ideozu Justin Eze,Geng Hua,Wang Yong,Yue Dan
A key player in mitochondrial respiration, p32, often referred to as C1QBP, is mostly found in the mitochondrial matrix. Previously, we showed that p32 interacts with DLAT in the mitochondria. Here, we found that p32 expression was reduced in ccRCC and suppressed progression and metastasis in ccRCC animal models. We observed that increasing p32 expression led to an increase in oxidative phosphorylation by interacting with DLAT, thus, regulating the activation of the pyruvate dehydrogenase complex (PDHc). Mechanistically, reduced p32 expression, in concert with DLAT, suppresses PDHc activity and the TCA cycle. Furthermore, our research discovered that p32 has a direct binding affinity for copper, facilitating the copper-induced oligomerization of lipo-DLAT specifically in ccRCC cells. This finding reveals an innovative function of the p32/DLAT/copper complex in regulating glycometabolism and the TCA cycle in ccRCC. Importantly, our research provides important new understandings of the underlying molecular processes causing the abnormal mitochondrial metabolism linked to this cancer.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
·
代谢紊乱
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产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2018
·
IF 6.383
Fengchun Tian,Fatima Zohra Dahmani,Jianan Qiao,Jiang Ni,Hui Xiong,Tengfei Liu,Jianping Zhou,Jing Yao
Several obstacles are currently impeding the successful treatment of breast cancer, namely impaired drug accumulation into the tumor site, toxicity to normal cells and narrow therapeutic index of chemotherapy, multidrug resistance (MDR) and the metastatic spread of cancer cells through the blood and lymphatic vessels. In this regard, we designed a novel multifunctional nano-sized drug delivery system based on LyP-1 peptide-modified low-molecular-weight heparin-quercetin conjugate (PLQ). This nanosystem was developed for targeted co-delivery of multiple anticancer drugs to p32-overexpressing tumor cells and peritumoral lymphatic vessels, using LyP-1 peptide as active targeting ligand, with the aim to achieve a targeted combinatorial chemo/angiostatic therapy and MDR reversal. The cellular uptake of PLQ nanoparticles by p32-overexpressing breast cancer cells was significantly higher than nonfunctionalized nanoparticles. Besides, the anti-angiogenic activity of PLQ nanoparticles was proven by the effective inhibition of the bFGF-induced neovascularization in subcutaneous Matrigel plugs. More importantly, PLQ/GA nanoparticles with better targeting ability toward p32-positive tumors, displayed a high antitumor outcome by inhibition of tumor cells proliferation and angiogenesis . Immunohistochemistry and western blot assay showed that PLQ/GA nanoparticles significantly disrupted the lymphatic formation of tumor, and inhibited the P-glycoprotein (P-gp) expression in MCF-7 tumor cells, respectively. In conclusion, PLQ/GA nanoparticles provide a synergistic strategy for effective targeted co-delivery of chemotherapeutic and antiangiogenic agents and reversing MDR and metastasis in breast cancer. Statement of Significance Herein, we successfully developed a novel amphiphilic nanomaterial , LyP-1-LMWH-Qu (PLQ) conjugate, consisting of a tumor-targeting moiety LyP-1, a hydrophobic quercetin (a multidrug resistance [MDR]–reversing drug) inner core, and a hydrophilic low-molecular-weight heparin (an antiangiogenic agent) outer shell for encapsulating and delivering a hydrophobic chemotherapeutic agent (gambogic acid). This versatile nanoplatform with multiple targeted features, i.e., dual chemo/angiostatic effects, destruction ability of the peritumoral lymphatic vessels, and reversal of MDR, resulted in a significantly stronger antitumor efficacy and lower toxic side effect than those of nontargeted nanoparticles and the free drug solution. Therefore, this versatile nanosystem might provide a novel insight for the treatment and palliation of breast cancer by targeted co-delivery of chemo/antiangiogenic agents and reversing MDR and metastasis.
研究领域:
肿瘤学
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药理学
·
纳米技术
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癌症治疗
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药物递送系统
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DOI
PubMed
高影响因子
Small
·
2023
·Vol. 19
·期 40
·2302834
·
IF 13.3
Kaipei Luo,Lu Yang,Chunmei Yan,Yuxin Zhao,Qiuxia Li,Xing Liu,Long Xie,Qiang Sun,Xiaofang Li
Immunotherapy gains increasing focus in treating triple-negative breast cancer (TNBC), while its efficacy is greatly restricted owing to low tumor immunogenicity and immunosuppressive tumor microenvironment (ITM). Herein, a LyP-1 and chondroitin sulfate (CS) dual-modified liposome co-loaded with paclitaxel (PTX) and cryptotanshinone (CTS), namely CS/LyP-1-PC Lip, is engineered for TNBC chemoimmunotherapy via induction of immunogenic cell death (ICD) and inhibition of signal transducer and activator of transcript-3 (STAT3) activation. CS/LyP-1-PC Lip enhances cellular uptake through p32 and CD44 dual receptor-mediated endocytosis. Within the tumor, the CS layer is continuously detached by hyaluronidase to release drugs. Subsequently, CTS sensitizes the cytotoxicity of PTX to 4T1 tumor cells. PTX induces ICD of tumor cells and facilitates infiltration of cytotoxic T lymphocyte to provoke immune response. Meanwhile, the concomitant delivery of CTS inhibits STAT3 activation to decrease infiltration of regulatory T cell, M2-type tumor-associated macrophage, and myeloid-derived suppressor cell, thus reversing ITM. Markedly, the dual-targeting liposome shows superior anti-tumor efficacy in subcutaneous TNBC mice and significant lung metastasis suppression in tumor metastasis model. Overall, this work offers a feasible combination regimen and a promising nanoplatform for the development of TNBC chemoimmunotherapy.
研究领域:
肿瘤学
·
药学
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免疫学
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纳米医学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）