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. 2023 Aug;50(8):6543-6556.
doi: 10.1007/s11033-023-08572-5. Epub 2023 Jun 20.

NKD1 targeting PCM1 regulates the therapeutic effects of homoharringtonine on colorectal cancer

Jia Cao  1   2 , Xiang Tao  3 , Bin Shi  4 , Jia Wang  1   2 , Rong Ma  1   2 , Jufen Zhao  3 , Jinhai Tian  1 , Qi Huang  1   2 , Jingjing Yu  1   2 , Libin Wang  5   6
Affiliations

NKD1 targeting PCM1 regulates the therapeutic effects of homoharringtonine on colorectal cancer

Jia Cao et al. Mol Biol Rep. 2023 Aug.

Abstract

Background: Colorectal cancer (CRC) is the most common primary malignancy. Recently, antineoplastic attributes of homoharringtonine (HHT) have attracted lots of attention. This study investigated the molecular target and underlying mechanism of HHT in the CRC process by using a cellular and animal models.

Methods: This study first detected the effects of HHT on the proliferation, cell cycle and apoptosis ability of CRC cells using CCK-8, Edu staining, flow cytometry and Western blotting assay. In vitro recovery experiment and in vivo tumorigenesis experiment were used to detect the targeted interaction between HHT and NKD1. After that, the downstream target and mechanism of action of HHT targeting NKD1 was determined using quantitative proteomics combined with co-immunoprecipitation/immunofluorescence assay.

Results: HHT suppressed CRC cells proliferation by inducing cell cycle arrest and apoptosis in vitro and vivo. HHT inhibited NKD1 expression in a concentration and time dependent manner. NKD1 was overexpressed in CRC and its depletion enhanced the therapeutic sensitivity of HHT on CRC, which indicating that NKD1 plays an important role in the development of CRC as the drug delivery target of HHT. Furthermore, proteomic analysis revealed that PCM1 participated the process of NKD1-regulated cell proliferation and cell cycle. NKD1 interacted with PCM1 and promoted PCM1 degradation through the ubiquitin-proteasome pathway. The overexpression of PCM1 effectively reversed the inhibition of siNKD1 on cell cycle.

Conclusions: The present findings revealed that HHT blocked NKD1 expression to participate in inhibiting cell proliferation and inducing cell apoptosis, ultimately leading to obstruction of CRC development through NKD1/PCM1 dependent mechanism. Our research provide evidence for clinical application of NKD1-targeted therapy in improving HHT sensitivity for CRC treatment.

Keywords: Apoptosis; Cell cycle; Colorectal cancer; Homoharringtonine; NKD1.

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References

    1. Fu M, Pan S, Cai X, Hu Y, Zhang W et al (2022) Analysis of ARHGAP4 expression with colorectal Cancer clinical characteristics and prognosis. Front Oncol 12:899837 - DOI - PubMed - PMC
    1. Xu M, Xu X, Pan B, Chen X, Lin K et al (2019) LncRNA SATB2-AS1 inhibits tumor metastasis and affects the tumor immune cell microenvironment in colorectal cancer by regulating SATB2. Mol Cancer 18(1):135 - DOI - PubMed - PMC
    1. Micu B, Vesa Ş, Pop T and C (2020) Micu. Evaluation of prognostic factors for 5 year-survival after surgery for colorectal cancer. Ann Ital Chir 91:41–48 - PubMed
    1. Li C, Dong L, Su R, Bi Y, Qing Y et al (2020) Homoharringtonine exhibits potent anti-tumor effect and modulates DNA epigenome in acute myeloid leukemia by targeting SP1/TET1/5hmC. Haematologica 105(1):148–160 - DOI - PubMed - PMC
    1. Gandhi V, Plunkett W, Cortes J (2014) Omacetaxine: a protein translation inhibitor for treatment of chronic myelogenous leukemia. Clin cancer research: official J Am Association Cancer Res 20(7):1735–1740 - DOI

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