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Tanshinones induce tumor cell apoptosis via directly targeting FHIT.

ABSTRACT: The liposoluble tanshinones are bioactive components in Salvia miltiorrhiza and are widely investigated as anti-cancer agents, while the molecular mechanism is to be clarified. In the present study, we identified that the human fragile histidine triad (FHIT) protein is a direct binding protein of sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of Tanshinone IIA (TSA), with a Kd value of 268.4 ± 42.59 nM. We also found that STS inhibited the diadenosine triphosphate (Ap3A) hydrolase activity of FHIT through competing for the substrate-binding site with an IC₅₀ value of 2.2 ± 0.05 µM. Notably, near 100 times lower binding affinities were determined between STS and other HIT proteins, including GALT, DCPS, and phosphodiesterase ENPP1, while no direct binding was detected with HINT1. Moreover, TSA, Tanshinone I (TanI), and Cryptotanshinone (CST) exhibited similar inhibitory activity as STS. Finally, we demonstrated that depletion of FHIT significantly blocked TSA's pro-apoptotic function in colorectal cancer HCT116 cells. Taken together, our study sheds new light on the molecular basis of the anti-cancer effects of the tanshinone compounds.

SUBMITTER: Zhou X

PROVIDER: S-EPMC8190080 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Tanshinones induce tumor cell apoptosis via directly targeting FHIT.

Zhou Xianglian X Pan Yuting Y Wang Yue Y Wang Bojun B Yan Yu Y Qu Yi Y Ke Xisong X

Scientific reports 20210609 1

The liposoluble tanshinones are bioactive components in Salvia miltiorrhiza and are widely investigated as anti-cancer agents, while the molecular mechanism is to be clarified. In the present study, we identified that the human fragile histidine triad (FHIT) protein is a direct binding protein of sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of Tanshinone IIA (TSA), with a Kd value of 268.4 ± 42.59 nM. We also found that STS inhibited the diadenosine triphosphate (Ap3A) hydro ...[more]

PMID: 34108553

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Project description:ObjectiveTo evaluate the antitumor capability and to investigate the underlying molecular mechanism of paclitaxel.MethodsFirst, cck-8 and apoptosis assays were used to determine survival and apoptotic effects of HS 737.T cells under treatment of paclitaxel. Next, RNA-seq and bioinformatics were used to determine the differentially expressed genes and to analyze the pathway involved. Quantitative real-time polymerase chain reaction was used to verify the accuracy of some differentially expressed genes (DEG). ClueGO was used to decode and visualize functionally grouped GO terms of differentially expressed genes, and to map the DEG protein-protein interactions (PPI) network. Western blotting was used to check the expression of target genes, the cleavage of Caspase-3 and PARP1, and the phosphorylation level of p53. Finally, transcriptomics, bioinformatics, and RNAi were used to estimate the antitumor capability and to identify the underlying mechanisms of paclitaxel in GCTB.ResultsOur data revealed that paclitaxel had significant time-dependent effects on the viability and induced apoptosis of HS 737.T cells. RNA-seq and bioinformatics analysis showed that apoptosis, death receptor signaling pathway, TNF signaling pathway, and TP53 regulated transcription of cell death genes pathway were closely associated with paclitaxel in the treatment of GCTB. Western bolt results revealed that paclitaxel induced cleavage of Caspase-3 and PARP1, and increased the phosphorylation level of p53 in HS 737.T cells. RNAi results showed that the expression level of TP53INP1 was significantly decreased in HS737.T cells (the decrease was more than 70%). In addition, we found that the inhibitory ratios of paclitaxel on HS737.T cells deficient in TP53INP1 were less than in HS737.T cells with empty vector (19.88 and 40.60%, respectively). Hence, our data revealed that TP53INP1 regulated paclitaxel-driven apoptosis in HS737.T cells.ConclusionPaclitaxel can significantly repress cell proliferation and induce apoptosis of HS 737.T cells through activating Caspase-3, PARP1, p53, and TP53INP1. Paclitaxel may be an effective drug in the management of GCTB.

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Tanshinones induce tumor cell apoptosis via directly targeting FHIT.

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Tanshinones induce tumor cell apoptosis via directly targeting FHIT.

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