Colorectal cancer (CRC) is one of the leading causes of malignancy-related deaths worldwide. Radiotherapy is often combined with surgery to treat patients with more advanced CRC. Despite impressive initial clinical responses, radiotherapy resistance is the main reason for most treatment failures in colorectal cancer. The G protein-coupled adrenergic receptor (AR) has shown to involve in the development and radiotherapy resistance of CRC. The β2-AR blockage (ICI-118,551) can use to inhibit the progression of CRC through downregulating EGFR-Akt-ERK1/2 signaling. Since catecholamines-activated the G protein-coupled AR activation has been shown to result in radioresistant, co-treatment with both β2-AR blockage and radiation may be improved the clinical outcome of CRC. We demonstrated that selective β2-AR blockage, but not selective β1-AR blockage, significantly enhanced radiation-induced apoptosis in CRC cells with wild-type p53 in vitro. The molecular mechanism of the apoptotic pathway was possibly triggered by a change in the mitochondrial membrane permeability and release of cytosolic cytochrome C through phospho-P53 mitochondrial translocation. We also found that a P53 knockout in the HCT116 cells was correlated with reversing β2-AR blockage-mediated apoptosis induction after radiation treatment. Furthermore, the β2-AR blockage significantly inhibited CRC cell-xenograft growth in vivo. Our study suggests that β2-AR blockage may be used as adjunct agent for improving the clinical outcomes of CRC following radiotherapy by inducing apoptosis in CRC cells.
Keywords: Colorectal cancer; P53; mitochondrial; radiotherapy; β2-adrenergic receptor.
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