Abstract
Radiotherapy is an important modality for the local control of human cancers, but the radioresistance induced by aberrant apoptotic signaling is a hallmark of cancers. Restoring the aberrant apoptotic pathways is an emerging strategy for cancer radiotherapy. In this study, we determined that targeting cell division cycle 20 (CDC20) radiosensitized colorectal cancer (CRC) cells through mitochondrial-dependent apoptotic signaling. CDC20 was overexpressed in CRC cells and upregulated after radiation. Inhibiting CDC20 activities genetically or pharmacologically suppressed the proliferation and increased radiation-induced DNA damage and intrinsic apoptosis in CRC cells. Mechanistically, knockdown of CDC20 suppressed the expression of antiapoptotic protein Mcl-1 but not other Bcl-2 family proteins. The expressions of CDC20 and Mcl-1 respond to radiation simultaneously through direct interaction, as evidenced by immunoprecipitation and glutathione S-transferase (GST) pull-down assays. Subsequently, decreased Mcl-1 expression inhibited the expression level of phosphorylated checkpoint kinase 1 (p-Chk1), thereby resulting in impaired DNA damage repair through downregulating the homologous recombination repair protein Rad51 and finally causing apoptotic signaling. In addition, both CDC20 and Chk1 inhibitors together, through in vivo studies, confirmed the radiosensitizing effect of CDC20 via inhibiting Mcl-1 and p-Chk1 expression. In summary, our results indicate that targeting CDC20 is a promising strategy to improve cancer radiotherapy.
Highlights
Radiation therapy is one of the three main approaches to cancer treatment
We noticed that Cell division cycle 20 (CDC20) expression in colorectal cancer (CRC) is especially higher, and increased CDC20 expression is closely related to the clinicopathological progression of CRC (Figure S1B,C, Supplementary Materials)
The Cancer Genome Atlas (TCGA) transcriptome data indicate that CDC20 is highly expressed in human cancers (Figure S1, Supplementary Materials)
Summary
Radiation therapy is one of the three main approaches to cancer treatment Factors such as radiation type/dose, radiosensitivity/radioresistance, clinical stage of cancer, and age of the patient can affect the outcome of radiotherapy [1]. Studies showed that APCCdc exerts its function in mitosis by targeting a variety of key cell-cycle regulators including securin and cyclin B for ubiquitin-mediated destruction [5,6]. CDC20 is overexpressed in a variety of human tumors including colorectal cancer (CRC) [8,9]. CDC20 governs apoptosis by mediating the degradation of phosphatidylcholine-specific phospholipase C in hepatocellular carcinoma cells [12]. These studies indicate that CDC20 is involved in the regulation of the cell cycle and apoptotic signaling. The detailed mechanism is unknown, and it is unclear whether CDC20 participates in the radiation response or affects CRC cell radiosensitivity
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