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Mitochondria in situ releasing corosolic acid enhanced antitumor effects via activating mitophagy in castration-resistant prostate cancer

ABSTRACT: Corosolic acid (CA) and its derivatives constitute a prominent class of drug candidates; however, their anticancer efficacy against resistant cancer types has been infrequently documented. Organelle-targeted drug delivery is a promising strategy to maximize anti-cancer effects and minimize adverse reactions. Herein, we report a mitochondria-targeted prodrug (CA-TPP) via an esterase-responsive phenolic ester bond to in situ release enough original drug (corosolic acid, CA) in mitochondria, and enhance the therapeutic efficacy. This mitochondria in situ releasing original drug theragnosis significantly reduced the treatment dose of CA to 25% both in vivo and in vitro. CA-TPP induces cell death in DU145 cells through mitochondrial-apoptosis pathway. RNA sequencing analysis further revealed that CA-TPP activated apoptosis through PINK1/Parkin-mediated mitophagy. Inhibition of mitophagy by PINK1 shRNA resulted in an alleviation in CA-TPP induced cytotoxicity in DU145 cells. Further mechanistic study indicates that ROS production in CA-TPP-treated cells causes mitochondrial apoptosis and mitophagy. Together, this prodrug design strategy obviously improved the specificity and anti-tumor activities, which provides a novel opportunity for cancer therapeutic development and broaden the targeted therapy options.

ORGANISM(S): Homo sapiens

PROVIDER: GSE315376 | GEO | 2026/05/15

REPOSITORIES: GEO

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Project description:This study aims to investigate the role and mechanism of DEK in asthmatic airway inflammation and in regulating PTEN-induced putative kinase 1 (PINK1)-Parkin mediated mitophagy, NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome activation, and apoptosis. We found that recombinant DEK protein (rmDEK) promoted eosinophils recruitment, mitochondrial fragmentation, and outer membrane 20 (TOM20) and LC3 co-localization representing mitophagosomes in bronchoalveolar lavage fluid (BALF) in house dust mite (HDM) induced-asthma. rmDEK also reduced co-localization of mitochondrial fusion protein mitofusin1 (MFN1) and mitochondria, and the protein level of manganese superoxide dismutase (MnSOD), enhanced microtubule-associated protein1 light chain 3 (LC3) and voltage-dependent anion channels (VDAC) co-localization which also represent the mitophagosomes in airway epithelial cells, furthermore, increased dynamin-related protein 1 (DRP1) expression, PINK1-Parkin-mediated mitophagy, NLRP3 inflammasome activation, and apoptosis. In the DEK knockout mice, HDM induced asthmatic airway inflammation, MnSOD, PINK1-Parkin protein level, Parkin mediated mitophagy characterized by LC3 and Parkin co-localization in the airways, ROS generation, NLRP3 inflammation and apoptosis were fully reversed. Similar effects of rmDEK were also observed in the BEAS-2B cells, which were rescued by the autophagy inhibitor 3-MA. Moreover, DEK silencing diminished the Parkin, LC3, DRP1 translocation to mitochondria; as well as mitochondrial ROS; TOM20 and mitochondrial DNA mediated mitochondrial oxidative damage. ChIP-sequence analysis showed that DEK was enriched on the AAA domain-containing protein 3A (ATAD3A) promoter and could positively regulate ATAD3A expression. Additionally, ATAD3A was highly expressed in HDM-induced asthma models. Furthermore, ATAD3A interacted with DRP1, and knockdown of ATAD3A could down-regulate DRP1 and mitochondrial oxidative damage. Conclusively, DEK deficiency alleviates airway inflammation in asthma by down-regulating PINK1-Parkin mitophagy, NLRP3 inflammasome activation, and apoptosis. The mechanism may be through the DEK/ATAD3A/DRP1 signaling axis. Our findings may provide new potential therapeutic targets for asthma treatment.

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Mitochondria in situ releasing corosolic acid enhanced antitumor effects via activating mitophagy in castration-resistant prostate cancer

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