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

Li, Kai; Zhang, Zhicheng; Yu, Mei; Yang, Qingzhu; Qiao, Shupei; Cheng, Ni; Yao, Yao; Li, Xinyuan; Li, Mengmeng; Wei, Dongdong; Fu, Wangyang; Guo, Xuefei; Huang, Xuemei; Yang, Huanjie

doi:10.7150/thno.51976

Cited by 18 publications

(15 citation statements)

References 49 publications

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“…Our previous study indicates that the chemoresistant PDAC cells secreted vital factors to enhance the resistance of the sensitive PDAC cells ( 19 ). To understand the molecular mechanism, we re-visited and analyzed our comparative secretome data, and obtained the network of proteins based on cell components and molecular function ( Supplementary Figures 1A, B ).…”

Section: Resultsmentioning

confidence: 99%

“…The plasmid pLVSIN-CMV-puro carrying GFP (pLVSIN-GFP) was constructed as described previously ( 19 ). pLVSIN-CMV-puro carrying RFP (pLVSIN-RFP) was constructed using the same approach.…”

Section: Methodsmentioning

confidence: 99%

“…To investigate the role of extracellular components in modulating gemcitabine resistance, we performed LC/MS using parental BxPC-3 and its subline BxPC-3-Gem which developed gemcitabine resistance ( 18 , 19 ) and found that MMP14 was a major differential protein shed by resistant BxPC-3-Gem cells versa parental BxPC-3 cells. As MMP14 is a membrane-bound protein, we hypothesized that MMP14 might be transferred via exosomes from chemoresistant PDAC cells, which might affect the chemoresistance of the surrounding PDAC sensitive cells.…”

Section: Introductionmentioning

confidence: 99%

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Chemoresistance Transmission via Exosome-Transferred MMP14 in Pancreatic Cancer

et al. 2022

Front. Oncol.

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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. Gemcitabine is the most commonly used chemotherapy for the treatment of PDAC, but the development of drug resistance still remains challenging. Recently, exosomes have emerged as important mediators for intercellular communication. Exosomes affect recipient cells’ behavior through the engulfed cargos, however the specific cargos responsible for gemcitabine resistance in PDAC are poorly understood. Here, we reported that exosomes could transfer gemcitabine resistance via a metalloproteinase 14 (MMP14)-dependent mechanism. MMP14 was identified as a major differentially secreted protein from the gemcitabine-resistant PDAC cells by comparative secretome. It was packaged into the exosomes and transmitted from the chemoresistant cells to the sensitive ones. The exosome-transferred MMP14 could enhance drug resistance and promotes the sphere-formation and migration abilities of the recipient sensitive PDAC cells. Mechanically, exosome-transferred MMP14 promotes the stability of CD44, the cancer stem cell marker in the recipient cells. Our results indicate that MMP14 is a key player for exosome-mediated transfer of gemcitabine resistance, thus targeting MMP14 in exosomes may represent a novel strategy to limit gemcitabine resistance in PDAC.

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Section: Resultsmentioning

confidence: 99%

“…The plasmid pLVSIN-CMV-puro carrying GFP (pLVSIN-GFP) was constructed as described previously ( 19 ). pLVSIN-CMV-puro carrying RFP (pLVSIN-RFP) was constructed using the same approach.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chemoresistance Transmission via Exosome-Transferred MMP14 in Pancreatic Cancer

et al. 2022

Front. Oncol.

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“…Gem has been widely utilized as a first-line drug for advanced pancreatic cancer for many years 6 , 22 . Although it has been shown to improve survival, many patients suffer from treatment failure due to severe drug resistance, in which an increase in NF-κB activity is a major chemoresistance mechanism 10 , 11 . Our above data show that alizarin could effectively inhibit the activity of NF-κB.…”

Section: Resultsmentioning

confidence: 99%

“…In this study, it was revealed for the first time that alizarin inhibited the growth of pancreatic cancer cells and induced cellular apoptosis by blocking the nuclear translocation of NF-κB and downregulating the related TNF-α-TAK1-NF-κB signaling cascade. According to multiple studies, the exceptional increase in NF-κB is one of the major mechanisms causing Gem resistance in the treatment of pancreatic cancer 10 , 11 . In our study, we demonstrate for the first time that alizarin combined with Gem has a synergistic effect in orthotopic pancreatic cancer mice.…”

Section: Introductionmentioning

confidence: 99%

Alizarin, a nature compound, inhibits the growth of pancreatic cancer cells by abrogating NF-κB activation

Xu¹,

Hou²,

C³

et al. 2022

Int. J. Biol. Sci.

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The current performance of nature compounds in antitumor field is gradually attracted more and more attention, we discovered a nature active ingredient alizarin possess potent natural reductive NF-κB activity to against pancreatic cancer. However, the preclinical pharmacology and therapeutic effect, and the underlying mechanisms of alizarin in inhibiting pancreatic cancer are still unclear. After high-throughput screening, this is the first report that alizarin can induce a potent inhibitory effect against pancreatic cancer cells. Alizarin induced cell cycle arrest and promoted cell apoptosis by inhibiting TNF-α-stimulated NF-κB activity and nuclear translocation, and inactivated its related TNF-α-TAK1-NF-κB signaling cascade followed by downregulation of NF-κB target genes involved in cell apoptosis (Bcl-2, Bcl-xL, XIAP) and in the cell cycle and growth (cyclin D, c-myc). Due to the abrogation of NF-κB activity, combination of alizarin and gemcitabine exerted a better inhibitory effect on pancreatic cancer. In summary, natural component alizarin, inhibited cell proliferation and induced apoptosis in vitro and in vivo through targeting of the NF-κB signaling cascade with minimal toxicity, which combine with gemcitabine, can significantly enhance the antitumor capability, playing a synergistic effect. Therefore, alizarin may play a role in reversing gemcitabine resistance caused by overactivated NF-κB in clinical application in the future.

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