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  1. Article ; Online: Co-delivery of Cas9 mRNA and guide RNAs for editing of LGMN gene represses breast cancer cell metastasis.

    Wang, Yue / Peng, Yatu / Zi, Guanghui / Chen, Jin / Peng, Baowei

    Scientific reports

    2024  Volume 14, Issue 1, Page(s) 8095

    Abstract: Legumain (or asparagine endopeptidase/AEP) is a lysosomal cysteine endopeptidase associated with increased invasive and migratory behavior in a variety of cancers. In this study, co-delivery of Cas9 mRNA and guide RNA (gRNA) by lipid nanoparticles (LNP) ... ...

    Abstract Legumain (or asparagine endopeptidase/AEP) is a lysosomal cysteine endopeptidase associated with increased invasive and migratory behavior in a variety of cancers. In this study, co-delivery of Cas9 mRNA and guide RNA (gRNA) by lipid nanoparticles (LNP) for editing of LGMN gene was performed. For in-vitro transcription (IVT) of gRNA, two templates were designed: linearized pUC57-T7-gRNA and T7-gRNA oligos, and the effectiveness of gRNA was verified in multiple ways. Cas9 plasmid was modified and optimized for IVT of Cas9 mRNA. The effects of LGMN gene editing on lysosomal/autophagic function and cancer cell metastasis were investigated. Co-delivery of Cas9 mRNA and gRNA resulted in impaired lysosomal/autophagic degradation, clone formation, migration, and invasion capacity of cancer cells in-vitro. Experimental lung metastasis experiment indicates co-delivery of Cas9 mRNA and gRNA by LNP reduced the migration and invasion capacity of cancer cells in-vivo. These results indicate that co-delivery of Cas9 mRNA and gRNA can enhance the efficiency of CRISPR/Cas9-mediated gene editing in-vitro and in-vivo, and suggest that Cas9 mRNA and gRNA gene editing of LGMN may be a potential treatment for breast tumor metastasis.
    MeSH term(s) Humans ; Female ; CRISPR-Cas Systems/genetics ; RNA, Guide, CRISPR-Cas Systems ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Breast Neoplasms/genetics ; Gene Editing/methods
    Chemical Substances RNA, Guide, CRISPR-Cas Systems ; RNA, Messenger
    Language English
    Publishing date 2024-04-06
    Publishing country England
    Document type Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-024-58765-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Hyperthermia and cisplatin combination therapy promotes caspase-8 accumulation and activation to enhance apoptosis and pyroptosis in cancer cells.

    Zi, Guanghui / Chen, Jin / Peng, Yatu / Wang, Yue / Peng, Baowei

    International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group

    2024  Volume 41, Issue 1, Page(s) 2325489

    Abstract: Background: Hyperthermia can play a synergistic role with chemotherapy in combination therapy. Although the association between caspase activation, apoptosis, and pyroptosis have been published for both cisplatin (CDDP) and hyperthermia therapies ... ...

    Abstract Background: Hyperthermia can play a synergistic role with chemotherapy in combination therapy. Although the association between caspase activation, apoptosis, and pyroptosis have been published for both cisplatin (CDDP) and hyperthermia therapies independently, the interactions between these molecular pathways in combination therapy are unknown. The present study aimed to investigate the possible interactions between caspase 8 activation, apoptosis, and pyroptosis in combination therapy.
    Methods: Cells were treated with CDDP (15 µg/ml), followed by hyperthermia at optimized temperature (42.5 °C) in water-bath. After combination therapy, cell viability was analyzed by CCK-8, and cell death was analyzed by Annexin-V-FITC/PI and caspases activation. Immuno-staining and co-immuno-precipitation were used to examine the interaction between p62 and caspase-8. Pyroptosis was investigated by western blotting and transmission electron microscopy. E3 ligase Cullin 3 was knockdown by siRNA. In addition, caspase-8 activation was modulated by CRISPR-Cas9 gene-editing or pharmacological inhibition.
    Results: Combination therapy promoted K63-linked polyubiquitination of caspase-8 and cellular accumulation of caspase-8. In turn, polyubiquitinated caspase-8 interacted with p62 and led to the activation of caspase-3. Knockdown of the E3 ligase Cullin 3 by siRNA reduced caspase-8 polyubiquitination and activation. In addition, combination therapy induced release of the pore-forming N-terminus from gasdermins and promoted pyroptosis along with caspase-8 accumulation and activation. Knockdown of caspase-8 by CRISPR/Cas9 based gene editing reduced the sensitivity of tumor cells to apoptosis and pyroptosis.
    Conclusions: Our study presented a novel mechanism in which hyperthermia synergized with chemotherapy in promoting apoptosis and pyroptosis in a caspase-8 dependent manner.
    MeSH term(s) Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Caspase 3/metabolism ; Caspase 3/pharmacology ; Caspase 8/drug effects ; Caspase 8/metabolism ; Cisplatin/pharmacology ; Cisplatin/therapeutic use ; Cullin Proteins/metabolism ; Hyperthermia, Induced ; Neoplasms/drug therapy ; Neoplasms/therapy ; Pyroptosis/drug effects ; RNA, Small Interfering
    Chemical Substances Antineoplastic Agents ; Caspase 3 (EC 3.4.22.-) ; Caspase 8 (EC 3.4.22.-) ; Cisplatin (Q20Q21Q62J) ; Cullin Proteins ; RNA, Small Interfering
    Language English
    Publishing date 2024-04-18
    Publishing country England
    Document type Journal Article
    ZDB-ID 632526-9
    ISSN 1464-5157 ; 0265-6736
    ISSN (online) 1464-5157
    ISSN 0265-6736
    DOI 10.1080/02656736.2024.2325489
    Database MEDical Literature Analysis and Retrieval System OnLINE

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