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Author: search.filters.author.Chanvorachote, PithiSubject: search.filters.subject.Lung cancer

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    Targeting multiple genes containing long mononucleotide A-T repeats in lung cancer stem cells
    (2021-12-01)
    Bhummaphan, Narumol
    ;
    Pin-on, Piyapat
    ;
    Phiboonchaiyanan, Preeyaporn Plaimee
    ;
    Siriluksana, Jirattha
    ;
    Aporntewan, Chatchawit
    Background: Intratumour heterogeneous gene expression among cancer and cancer stem cells (CSCs) can cause failure of current targeted therapies because each drug aims to target the function of a single gene. Long mononucleotide A-T repeats are cis-regulatory transcriptional elements that control many genes, increasing the expression of numerous genes in various cancers, including lung cancer. Therefore, targeting A-T repeats may dysregulate many genes driving cancer development. Here, we tested a peptide nucleic acid (PNA) oligo containing a long A-repeat sequence [A(15)] to disrupt the transcriptional control of the A-T repeat in lung cancer and CSCs. Methods: First, we separated CSCs from parental lung cancer cell lines. Then, we evaluated the role of A-T repeat gene regulation by counting the number of repeats in differentially regulated genes between CSCs and the parental cells of the CSCs. After testing the dosage and effect of PNA-A15 on normal and cancer cell toxicity and CSC phenotypes, we analysed genome-wide expression to identify dysregulated genes in CSCs. Results: The number of A-T repeats in genes differentially regulated between CSCs and parental cells differed. PNA-A15 was toxic to lung cancer cells and CSCs but not to noncancer cells. Finally, PNA-A15 dysregulated a number of genes in lung CSCs. Conclusion: PNA-A15 is a promising novel targeted therapy agent that targets the transcriptional control activity of multiple genes in lung CSCs.
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    Titania nanosheet generates peroxynitrite-dependent S-nitrosylation and enhances p53 function in lung cancer cells
    (2021-08-01)
    Soonnarong, Rapeepun
    ;
    Tungsukruthai, Sucharat
    ;
    Nutho, Bodee
    ;
    Rungrotmongkol, Thanyada
    ;
    Vinayanuwattikun, Chanida
    Metal nanomaterials can enhance the efficacy of current cancer therapies. Here, we show that Ti<inf>0.8</inf> O<inf>2</inf> nanosheets cause cytotoxicity in several lung cancer cells but not in normal cells. The nanosheet-treated cells showed certain apoptosis characteristics. Protein analysis further indicated the activation of the p53-dependent death mechanism. Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) analyses revealed the cellular uptake of the nanosheets and the induction of cell morphological change. The nanosheets also exhibited a substantial apoptosis effect on drug-resistant metastatic primary lung cancer cells, and it was found that the potency of the nanosheets was dramatically higher than standard drugs. Ti<inf>0.8</inf> O<inf>2</inf> nanosheets induce apoptosis through a molecular mechanism involving peroxynitrite (ONOO<sup>−</sup>) generation. As peroxynitrite is known to be a potent inducer of S-nitrosylation, we further found that the nanosheets mediated the S-nitrosylation of p53 at C182, resulting in higher protein-protein complex stability, and this was likely to induce the surrounding residues, located in the interface region, to bind more strongly to each other. Molecular dynamics analysis revealed that S-nitrosylation stabilized the p53 dimer with a ∆Gbind<sup>residue</sup> of <−1.5 kcal/mol. These results provide novel insight on the apoptosis induction effect of the nanosheets via a molecular mechanism involving S-nitrosylation of the p53 protein, emphasizing the mechanism of action of nanomaterials for cancer therapy.