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Pine needle hexane extract promote cell cycle arrest and premature senescence via p27^KIP1 upregulation gastric cancer cells.

ABSTRACT: Pinus densiflora sieb. et zucc.(pine needle) is a traditional medicine used in several East Asian countries. However, the efficacy of pine needle has rarely been reported. In this study showed that the anti-proliferative effects and the mechanisms of hexane layer of pine needle MeOH extract (PNH) on gastric cancer cells. At first, PNH inhibited the proliferation of gastric cancer cells in a dose-dependent manner. Moreover, PNH treatment induced G1 phase cell cycle arrest through the increased p27^KIP1 expression and decreased cyclin dependent kinase (CDKs) activity. Furthermore, PNH treatment induced premature senescence without oncogenic stress, through the expression of p27^KIP1 and Skp2. Taken together, these results showed that PNH inhibited gastric cancer cell proliferation through the induction of G1-cell cycle arrest and premature senescence via induced p27^KIP1 expression, as controlled by Skp2 reduction. Also, PNH could be a candidate for anti-gastric cancer treatment and may be useful in the development of anti-gastric cancer drugs.

SUBMITTER: Kim W

PROVIDER: S-EPMC7256146 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Pine needle hexane extract promote cell cycle arrest and premature senescence via p27<sup>KIP1</sup> upregulation gastric cancer cells.

Kim Woong W Park Cheolwoo C Park Jaeyoung J Cheong Hyeonsook H Kim Seok-Jun SJ

Food science and biotechnology 20200205 6

<i>Pinus densiflora sieb. et zucc.</i>(pine needle) is a traditional medicine used in several East Asian countries. However, the efficacy of pine needle has rarely been reported. In this study showed that the anti-proliferative effects and the mechanisms of hexane layer of pine needle MeOH extract (PNH) on gastric cancer cells. At first, PNH inhibited the proliferation of gastric cancer cells in a dose-dependent manner. Moreover, PNH treatment induced G1 phase cell cycle arrest through the incre ...[more]

PMID: 32523794

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Project description:Background & aimsOncogenic mutations in KRAS, coupled with inactivation of p53, CDKN2A/p16INK4A, and SMAD4, drive progression of pancreatic ductal adenocarcinoma (PDA). Overexpression of MYC and deregulation of retinoblastoma (RB) further promote cell proliferation and make identifying a means to therapeutically alter cell-cycle control pathways in PDA a significant challenge. We previously showed that the basic helix-loop-helix transcription factor E47 induced stable growth arrest in PDA cells in vitro and in vivo. Here, we identified molecular mechanisms that underlie E47-induced growth arrest in low-passage, patient-derived primary and established PDA cell lines.MethodsRNA sequencing was used to profile E47-dependent transcriptomes in 5 PDA cell lines. Gene Ontology analysis identified cell-cycle control as the most altered pathway. Small interfering RNA/short hairpin RNA knockdown, small-molecule inhibitors, and viral expression were used to examine the function of E47-dependent genes in cell-cycle arrest. Cell morphology, expression of molecular markers, and senescence-associated β-galactosidase activity assays identified cellular senescence.ResultsE47 uniformly inhibited PDA cell-cycle progression by decreasing expression of MYC, increasing the level of CDKN1B/p27KIP1, and restoring RB tumor-suppressor function. The molecular mechanisms by which E47 elicited these changes included altering both RNA transcript levels and protein stability of MYC and CDKN1B/p27KIP1. At the cellular level, E47 elicited a senescence-like phenotype characterized by increased senescence-associated β-galactosidase activity and altered expression of senescence markers.ConclusionsE47 governs a highly conserved network of cell-cycle control genes, including MYC, CDKN1B/p27KIP1, and RB, which can induce a senescence-like program in PDA cells that lack CDKN2A/p16INK4A and wild-type p53. RNA sequencing data are available at the National Center for Biotechnology Information GEO at https://www.ncbi.nlm.nih.gov/geo/; accession number: GSE100327.

Project description:BackgroundPoly C Binding Protein 1 (PCBP1) is an RNA-binding protein that binds and regulates translational activity of subsets of cellular mRNAs. Depletion of PCBP1 is implicated in various carcinomas, but the underlying mechanism in tumorigenesis remains elusive.MethodsWe performed a transcriptome-wide screen to identify novel bounding mRNA of PCBP1. The bind regions between PCBP1 with target mRNA were investigated by using point mutation and luciferase assay. Cell proliferation, cell cycle, tumorigenesis and cell apoptosis were also evaluated in ovary and colon cancer cell lines. The mechanism that PCBP1 affects p27 was analyzed by mRNA stability and ribosome profiling assays. We analyzed PCBP1 and p27 expression in ovary, colon and renal tumor samples and adjacent non-tumor tissues using RT-PCR, Western Blotting and immunohistochemistry. The prognostic significance of PCBP1 and p27 also analyzed using online databases.ResultsWe identified cell cycle inhibitor p27Kip1 (p27) as a novel PCBP1-bound transcript. We then demonstrated that binding of PCBP1 to p27 3'UTR via its KH1 domain mainly stabilizes p27 mRNA, while enhances its translation to fuel p27 expression, prior to p27 protein degradation. The upregulated p27 consequently inhibits cell proliferation, cell cycle progression and tumorigenesis, whereas promotes cell apoptosis under paclitaxel treatment. Conversely, knockdown of PCBP1 in turn compromises p27 mRNA stability, leading to lower p27 level and tumorigenesis in vivo. Moreover, forced depletion of p27 counteracts the tumor suppressive ability of PCBP1 in the same PCBP1 over-expressing cells. Physiologically, we showed that decreases of both p27 mRNA and its protein expressions are well correlated to PCBP1 depletion in ovary, colon and renal tumor samples, independent of the p27 ubiquitin ligase Skp2 level. Correlation of PCBP1 with p27 is also found in the tamoxifen, doxorubincin and lapatinib resistant breast cancer cells of GEO database.ConclusionOur results thereby indicate that loss of PCBP1 expression firstly attenuates p27 expression at post-transcriptional level, and subsequently promotes carcinogenesis. PCBP1 could be used as a diagnostic marker to cancer patients.

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Pine needle hexane extract promote cell cycle arrest and premature senescence via p27^KIP1 upregulation gastric cancer cells.

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Pine needle hexane extract promote cell cycle arrest and premature senescence via p27<sup>KIP1</sup> upregulation gastric cancer cells.

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Pine needle hexane extract promote cell cycle arrest and premature senescence via p27KIP1 upregulation gastric cancer cells.

Publications

Pine needle hexane extract promote cell cycle arrest and premature senescence via p27<sup>KIP1</sup> upregulation gastric cancer cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Pine needle hexane extract promote cell cycle arrest and premature senescence via p27^KIP1 upregulation gastric cancer cells.