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Metallothionein-1G suppresses pancreatic cancer cell stemness by limiting activin A secretion via NF-?B inhibition.

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-?B 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-?B-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-?B target, was highly secreted by drug resistant cells. It promotes pancreatic cancer stemness in Smad4-dependent or independent manners. Mechanistically, MT1G negatively regulates NF-?B signaling and promotes the degradation of NF-?B 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-?B inhibition. The blockade of the activin A signaling with follistatin may provide a promising therapeutic strategy for overcoming gemcitabine resistance in PDAC.

SUBMITTER: Li K

PROVIDER: S-EPMC7847690 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Metallothionein-1G suppresses pancreatic cancer cell stemness by limiting activin A secretion <i>via</i> NF-κB inhibition.

Li Kai K Zhang Zhicheng Z Mei Yu Y Yang Qingzhu Q Qiao Shupei S Ni Cheng C Yao Yao Y Li Xinyuan X Li Mengmeng M Wei Dongdong D Fu Wangjun W Guo Xuefei X Huang Xuemei X Yang Huanjie H

Theranostics 20210101 7

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). <b>Methods:</b> MT1G was identified as a critical factor related with gemcitabine resistance in PDAC cells by mRNA microarray. Its effects on P ...[more]

PMID: 33537082

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Dataset Information

Metallothionein-1G suppresses pancreatic cancer cell stemness by limiting activin A secretion via NF-?B inhibition.

Publications

Metallothionein-1G suppresses pancreatic cancer cell stemness by limiting activin A secretion <i>via</i> NF-κB inhibition.

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