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Responsive calcium-derived nanoassemblies induce mitochondrial disorder to promote tumor calcification.

ABSTRACT: Physiological calcification of the treated tumor area is considered to be a predictor of good prognosis. Promoting tumor calcification by inducing mitochondrial metabolic disorder and destroying calcium equilibrium has a potential inhibitory effect on tumor proliferation. Here, by promoting calcification by inducing mitochondrial dysfunction combined with triggering a surge of reactive oxygen species, we construct a bioresponsive calcification initiator, termed CaP-AA, using CaHPO₄ covalently doped l-ascorbic acid. CaHPO₄ releases Ca²⁺ within the cytoplasm of tumor cells to trigger calcium overload. Meanwhile, exogenous l-ascorbic acid indirectly enhances metabolic balance disruption via pro-oxidant effects. Such Ca²⁺ overload increases the likelihood of tumor calcification in vivo for tumor inhibition by perturbing mitochondrial homeostasis. The introduction of responsive calcium sources that would, in turn, trigger intratumoral calcification mediated by perturbing mitochondrial homeostasis would be an effective regulatory strategy for tumor therapy.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC10498499 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Responsive calcium-derived nanoassemblies induce mitochondrial disorder to promote tumor calcification.

Zhao Yan Y Yu Xinquan X Kong Weiheng W Kong Rong-Mei RM Zhang Ensheng E Xia Lian L Zhang Jing J Qu Fengli F Tan Weihong W

Chemical science 20230823 35

Physiological calcification of the treated tumor area is considered to be a predictor of good prognosis. Promoting tumor calcification by inducing mitochondrial metabolic disorder and destroying calcium equilibrium has a potential inhibitory effect on tumor proliferation. Here, by promoting calcification by inducing mitochondrial dysfunction combined with triggering a surge of reactive oxygen species, we construct a bioresponsive calcification initiator, termed CaP-AA, using CaHPO<sub>4</sub> co ...[more]

PMID: 37712028

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Project description:Rationale: High neutrophil infiltration in hepatocellular carcinoma (HCC) is associated with a poor prognosis in patients with HCC. Tumor-derived exosomes (TDEs) have been proven to be important in the reprogramming of tumor-associated neutrophils (TANs), but the roles and mechanisms have not been fully clarified. Methods: The roles of HCC-exosome-reprogrammed neutrophils on tumor progression were evaluated in the DEN/CCl4-induced HCC mouse model by blocking neutrophil infiltration, depleting neutrophil, and neutrophil adoptive transfer. Transcriptome sequencing and flow cytometry were performed to investigate the effects of HCC exosomes on the phenotype and function of neutrophils. The mobilization and apoptosis of neutrophils were evaluated by the Transwell experiment and Annexin V/7-AAD staining, respectively. Moreover, we detected the effects of HCC-exosome-reprogrammed neutrophils on T cells by flow cytometry. Next, we used the NF-κB pathway inhibitor JSH-23 and miR-362-5p inhibitor or mimic to determine the molecular mechanisms. Lastly, we constructed the miR-362-5p sponge to validate its targeted therapeutic potential. Results: We found that HCC exosomes induced neutrophil infiltration and T-cell exhaustion in the livers of DEN/CCl4-induced HCC mice and promoted tumor progression. Blocking neutrophil infiltration and depleting neutrophils diminished these promotive effects of HCC exosomes. In addition, HCC exosome-reprogrammed neutrophils display proinflammatory and protumor phenotypes, and can directly induce T-cell exhaustion in vitro. The transfer of HCC exosome-reprogrammed neutrophils exacerbated tumor progression and induced T-cell exhaustion, as evidenced by the downregulation of IFN-γ and TNF-α, and the upregulation of PD-1 and Tim3 in T cells. Mechanistically, we found that HCC exosomes upregulate the expression of miR-362-5p in neutrophils and activate the NF-κB signaling pathway by targeting CYLD, promoting the survival and recruitment of neutrophils. In HCC mice, blocking miR-362-5p suppressed neutrophil infiltration, attenuated T-cell exhaustion, and suppressed HCC progression. Conclusions: This study clarified the roles of HCC exosomes on neutrophil infiltration and reprogramming and identified a potential target miR-362-5p for HCC treatment.

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Responsive calcium-derived nanoassemblies induce mitochondrial disorder to promote tumor calcification.

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Responsive calcium-derived nanoassemblies induce mitochondrial disorder to promote tumor calcification.

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