title: Acquisition of Chemoresistance and Other Malignancy-related Features of Colorectal Cancer Cells Are Incremented by Ribosome-inactivating Stress.
abstract: Colorectal cancer (CRC) as an environmental disease is largely influenced by accumulated epithelial stress from diverse environmental causes. We are exposed to ribosome-related insults, including ribosome-inactivating stress (RIS), from the environment, dietary factors, and medicines, but their physiological impacts on the chemotherapy of CRC are not yet understood. Here we revealed the effects of RIS on chemosensitivity and other malignancy-related properties of CRC cells. First, RIS led to bidirectional inhibition of p53-macrophage inhibitory cytokine 1 (MIC-1)-mediated death responses in response to anticancer drugs by either enhancing ATF3-linked antiapoptotic signaling or intrinsically inhibiting MIC-1 and p53 expression, regardless of ATF3. Second, RIS enhanced the epithelial-mesenchymal transition and biogenesis of cancer stem-like cells in an ATF3-dependent manner. These findings indicate that gastrointestinal exposure to RIS interferes with the efficacy of chemotherapeutics, mechanistically implying that ATF3-linked malignancy and chemoresistance can be novel therapeutic targets for the treatment of environmentally aggravated cancers.
authors.affiliation: From the Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences and Medical Research Institute, Pusan National University School of Medicine, Yangsan 50612, South Korea.
authors.forename: Chang-Kyu
authors.initials: CK
authors.lastname: Oh
authors.affiliation: From the Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences and Medical Research Institute, Pusan National University School of Medicine, Yangsan 50612, South Korea.
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: From the Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences and Medical Research Institute, Pusan National University School of Medicine, Yangsan 50612, South Korea.
authors.forename: Seong-Hwan
authors.initials: SH
authors.lastname: Park
authors.affiliation: From the Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences and Medical Research Institute, Pusan National University School of Medicine, Yangsan 50612, South Korea moon@pnu.edu.
authors.forename: Yuseok
authors.initials: Y
authors.lastname: Moon
mesh_terms: D051700:Activating Transcription Factor 3 / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D055436:Growth Differentiation Factor 15 / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D012270:Ribosomes / Q000378:metabolism*; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: activating transcription factor 3 (ATF3); chemoresistance; colorectal cancer; macrophage inhibitory cytokine 1 (MIC-1); ribosome-inactivating stress (RIS); toxicity; toxicology; toxin