Abstract
Colorectal cancer (CRC) is one of the most common malignancies in the world and has a poor prognosis. In the present research, gambogenic acid (GNA), isolated from the traditional Chinese medicine gamboge, markedly induced apoptosis and inhibited the proliferation of CRC in vitro and in vivo. Furthermore, GNA triggered endoplasmic reticulum (ER) stress, which subsequently activated inositol-requiring enzyme (IRE) 1α and the eukaryotic translation initiation factor (eIF) 2α pathway. Pretreatment with salubrinal (an eIF2α inhibitor) rescued GNA-induced cell death. Furthermore, GNA downregulated the expression of Aurora A. The Aurora A inhibitor alisertib decreased ER stress. In human colorectal adenocarcinoma tissue, Aurora A was upregulated compared to normal colorectal epithelial nuclei. Furthermore, GNA ameliorated mouse colitis-associated cancer models. Our findings demonstrated that GNA significantly inhibited the proliferation of CRC through activation of ER stress by regulating Aurora A, which indicates the potential of GNA for preventing the progression of CRC.
Highlights
Colorectal cancer (CRC) is the most common malignant tumour of the gastrointestinal tract and has become the third most common malignant tumour worldwide (Keum and Giovannucci, 2019)
We considered that endoplasmic reticulum (ER) stress was induced by gambogenic acid (GNA) treatment in HCT116 cells
GNA remarkably inhibited the proliferation of cancer, promoted cell apoptosis and cell cycle arrest (Huang et al, 2019) and overcame cisplatin resistance (Shen et al, 2020)
Summary
Colorectal cancer (CRC) is the most common malignant tumour of the gastrointestinal tract and has become the third most common malignant tumour worldwide (Keum and Giovannucci, 2019). The majority of patients discover disease after local or distant metastasis and miss opportunities for surgical treatment (Hosseini et al, 2016; Siegel et al, 2017). The treatment of advanced stage CRC is mainly adjuvant chemotherapy, but common chemotherapy regimens have obvious side effects. The 5-year survival rate ranges from 90% of patients with localised disease to more than 14% of patients with distant-stage disease (Siegel et al, 2020). Despite tremendous progress in medical treatments, the influence of these treatments on the cure rate and long-term survival rate of CRC is limited. The development of novel CRC drugs is urgently needed
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