Macrophage inhibitory cytokine-1 (MIC-1) and subsequent urokinase-type plasminogen activator mediate cell death responses by ribotoxic anisomycin in HCT-116 colon cancer cells.
Ribosome-inactivating stresses possess a potent regulatory activity against tumor cell progression. In this study, we demonstrated that macrophage inhibitory cytokine-1 (MIC-1) and its associated signals determined the colon cancer cell response to the chemical ribotoxic stress. The ribotoxic stress agent anisomycin-induced MIC-1 gene expression which was involved in the ribotoxin-induced apoptotic pathway. MIC-1 was also a critical inducer of apoptosis-related gene products such as activated urokine-type plasminogen activator (PLAU) and PLAU receptor (uPAR). When MIC-1 or PLAU action was repressed in the tumor cells, the chemical ribotoxic stress triggered a survival-related MAP kinase such as ERK. Mechanistically, gene expression of apoptosis-mediator MIC-1 was enhanced by activating transcription factor 3 (ATF-3) via the p38 MAP kinase signaling pathway. Moreover, both promoter activity and mRNA stability of MIC-1 gene were up-regulated by ribotoxic anisomycin via the p38 MAP kinase signaling pathway. In conclusion, ribotoxic anisomycin-induced MIC-1 expression via p38-ATF3 pathway and subsequent apoptosis while suppressing survival ERK signal in the colon cancer cells. The results of this study provide mechanistic insight into tumor cell decision for death or survival pathways in response to ribosome-disrupting stresses from chemotherapeutics.
Yang
Hyun
H
Department of Microbiology and Immunology and Medical Research Institute, Pusan National University School of Medicine, Yangsan, Republic of Korea.
Choi
Hye Jin
HJ
Park
Seong Hwan
SH
Kim
Jong Sik
JS
Moon
Yuseok
Y
D000841:Anisomycin / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D002453:Cell Cycle; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D017931:DNA Primers; D005434:Flow Cytometry; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008856:Microscopy, Fluorescence; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D017931:DNA Primers; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D000841:Anisomycin; D048051:p38 Mitogen-Activated Protein Kinases