Chemoresistance and stemness of colorectal cancer cells are acquired after ribosome-inactivating stress
Pusan National University School of Medicine
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 mycotoxins and antibiotics, 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 expressions, regardless of ATF3. Second, RIS enhanced epithelial mesenchymal transition (EMT) and biogenesis of cancer stem-like cells (CSC) in an ATF3-dependent manner. These findings indicated that gastrointestinal exposure to RIS interferes with the efficacy of chemotherapeutics, mechanistically implicating that ATF3-linked malignancy and chemoresistance can be novel therapeutic targets for treatment of environmentally aggravated cancers (This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and future Planning (NRF-2015R1A2A1A15056056) and the Ministry of Education (NRF-2016R1A6A3A11932208)).