1. Metallothionein-1G suppresses pancreatic cancer cell stemness by limiting activin A secretion via NF-κB inhibition.
- Author
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Li K, Zhang Z, Mei Y, Yang Q, Qiao S, Ni C, Yao Y, Li X, Li M, Wei D, Fu W, Guo X, Huang X, and Yang H
- Subjects
- Animals, Carcinoma, Pancreatic Ductal pathology, Cell Line, Tumor, China, Chromatography, Liquid, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, Female, Humans, Metallothionein genetics, Mice, Inbred C57BL, Mice, Nude, NF-kappa B metabolism, Neoplastic Stem Cells physiology, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Signal Transduction drug effects, Tandem Mass Spectrometry, Transcription Factor RelA metabolism, Xenograft Model Antitumor Assays, Mice, Activins metabolism, Metallothionein metabolism, Neoplastic Stem Cells metabolism
- Abstract
Resistance to chemotherapy is a long-standing problem in the management of cancer, and cancer stem cells are regarded as the main source of this resistance. This study aimed to investigate metallothionein (MT)-1G involvement in the regulation of cancer stemness and provide a strategy to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC). Methods: MT1G was identified as a critical factor related with gemcitabine resistance in PDAC cells by mRNA microarray. Its effects on PDAC stemness were evaluated through sphere formation and tumorigenicity. LC-MS/MS analysis of conditional medium revealed that activin A, a NF-κB target, was a major protein secreted from gemcitabine resistant PDAC cells. Both loss-of-function and gain-of-function approaches were used to validate that MT1G inhibited NF-κB-activin A pathway. Orthotopic pancreatic tumor model was employed to explore the effects on gemcitabine resistance with recombinant follistatin to block activin A. Results: Downregulation of MT1G due to hypermethylation of its promoter is related with pancreatic cancer stemness. Secretome analysis revealed that activin A, a NF-κB target, was highly secreted by drug resistant cells. It promotes pancreatic cancer stemness in Smad4-dependent or independent manners. Mechanistically, MT1G negatively regulates NF-κB signaling and promotes the degradation of NF-κB p65 subunit by enhancing the expression of E3 ligase TRAF7. Blockade of activin A signaling with follistatin could overcome gemcitabine resistance. Conclusions: MT1G suppresses PDAC stemness by limiting activin A secretion via NF-κB inhibition. The blockade of the activin A signaling with follistatin may provide a promising therapeutic strategy for overcoming gemcitabine resistance in PDAC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)
- Published
- 2021
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