PP2A inhibitors induce apoptosis in pancreatic cancer cell line PANC-1 through persistent phosphorylation of IKKα and sustained activation of the NF-κB pathway

Li, Wei; Chen, Zheng; Zong, Yang; Gong, Fei‐Ran; Zhu, Yaping; Zhu, Yunxia; Lv, Jinghuan; Zhang, Jingjing; Xie, Li; Sun, Yujie; Miao, Yi; Tao, Min; Han, Xiao; Xu, Zekuan

doi:10.1016/j.canlet.2011.02.009

Cited by 48 publications

(62 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…11 Higher phosphorylation levels of IKK were found in the DBTC-treated group ( Figure 2F), suggesting NF-kB pathway activation. As expected, PP2Ac expression was repressed in the DBTC-treated group ( Figure 2F), suggesting PP2Ac regulation could be involved in inflammation-driven pancreatic cancer progression.…”

Section: Inflammatory Stimuli Promoted Pancreatic Cancer Cell Growth mentioning

confidence: 90%

“…Furthermore, PP2Ac overexpression induced apoptosis and repressed pancreatic cancer cell growth. 6,11 These results suggested that PP2A plays a tumor suppressor role and could be a potential target for cancer treatment.…”

Section: Introductionmentioning

confidence: 85%

“…16 Moreover, the carcinogenesis effect of TAM has been proved to be related to activation of NF-kB pathway. 17 According to the canonical NF-kB pathway cascade, 11 the phosphorylated IkB kinase (IKK) can further phosphorylate IkB, which is the cytoplasmic inhibitor of the NF-kB complex. When phosphorylated, IkB undergoes ubiquitination and proteasome-mediated degradation rapidly, resulting in the release and nuclear translocation of the NF-kB complex.…”

Section: Introductionmentioning

confidence: 99%

“…Once inside the nucleus, p65 engages the cognate kB enhancers, which contain one or more kB-enhancer consensus sequences (5 0 -GGGRNYYYCC-3 0 , where R is a purine, Y is a pyrimidine, and N is any nucleic acid), and regulates the expression of downstream genes. 11,18,19 Whether LPS-induced PP2A repression can be mediated in a NF-kB pathway-dependent manner has not been explored.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

et al. 2016

Self Cite

View full text Add to dashboard Cite

Previous studies have indicated that inflammatory stimulation represses protein phosphatase 2A (PP2A), a well-known tumor suppressor. However, whether PP2A repression participates in pancreatic cancer progression has not been verified. We used lipopolysaccharide (LPS) and macrophage-conditioned medium (MCM) to establish in vitro inflammation models, and investigated whether inflammatory stimuli affect pancreatic cancer cell growth and invasion PP2A catalytic subunit (PP2Ac)-dependently. Via nude mouse models of orthotopic tumor xenografts and dibutyltin dichloride (DBTC)-induced chronic pancreatitis, we evaluated the effect of an inflammatory microenvironment on PP2Ac expression in vivo. We cloned the PP2Aca and PP2Acb isoform promoters to investigate the PP2Ac transcriptional regulation mechanisms. MCM accelerated pancreatic cancer cell growth; MCM and LPS promoted cell invasion. DBTC promoted xenograft growth and metastasis, induced tumor-associated macrophage infiltration, promoted angiogenesis, activated the nuclear factor-kB (NF-kB) pathway, and repressed PP2Ac expression. In vitro, LPS and MCM downregulated PP2Ac mRNA and protein. PP2Aca overexpression attenuated JNK, ERK, PKC, and IKK phosphorylation, and impaired LPS/MCM-stimulated cell invasion and MCM-promoted cell growth. LPS and MCM activated the NF-kB pathway in vitro. LPS and MCM induced IKK and IkB phosphorylation, leading to p65/RelA nuclear translocation and transcriptional activation. Overexpression of the dominant negative forms of IKKa attenuated LPS and MCM downregulation of PP2Ac, suggesting inflammatory stimuli repress PP2Ac expression NF-kB pathway-dependently. Luciferase reporter gene assay verified that LPS and MCM downregulated PP2Ac transcription through an NF-kB-dependent pathway. Our study presents a new mechanism in inflammation-driven cancer progression through NF-kB pathway-dependent PP2Ac repression.

show abstract

Section: Inflammatory Stimuli Promoted Pancreatic Cancer Cell Growth mentioning

confidence: 90%

Section: Introductionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…133,134 Inhibition of PP2A with cantharidins has been previously shown to suppress growth of pancreatic cancer cells in vitro through sustained activation of the NF-kB pathway, hyperactivation of the c-Jun/JNK pathway, and inhibition of the Wnt/B-catenin pathway. 11,135,136 Based on these findings, PP2A inhibition was studied in pancreatic cancer cells for its potential as a radiosensitizing agent. Via high-throughput siRNA library screen in human pancreatic cancer cells, Wei et al identified depletion of the subunit PPP2R1A as a significant sensitizer to gemcitabine and radiation.…”

Section: Pancreatic Cancermentioning

confidence: 99%

LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential

Zhang

et al. 2015

Cancer Biology & Therapy

103

View full text Add to dashboard Cite

Berberine attenuates pulmonary arterial hypertension via protein phosphatase 2A signaling pathway both in vivo and in vitro

Luo

Liu

et al. 2018

Journal Cellular Physiology

View full text Add to dashboard Cite

Excessive proliferation, migration, and antiapoptosis of pulmonary artery (PA) smooth muscle cells (PASMCs) underlies the development of pulmonary vascular remodeling. The innervation of the PA is predominantly sympathetic, and increased levels of circulating catecholamines have been detected in pulmonary arterial hypertension (PAH), suggesting that neurotransmitters released by sympathetic overactivation may play an essential role in PAH. However, the responsible mechanism remains unclear. Here, to investigate the effects of norepinephrine (NE) on PASMCs and the related mechanism, we used 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, the proliferating cell nuclear antigen and the cell counting kit-8 assay to evaluate the proliferation of PASMCs, Boyden chamber migration, and wound-healing assays to assess migration and western blot analysis to investigate protein expression. We demonstrated that the phosphorylation level of the protein phosphatase 2A (PP2A) catalytic subunit (Y307) was higher in PAH patients and PAH models than in controls, both in vivo and in vitro. In addition, NE induced the proliferation and migration of PASMCs, which was attenuated by berberine (BBR), a Chinese herbal medicine, and/or PP2A overexpression. PP2A inhibition worsened NE-induced PAH and could not be reversed by BBR. Thus, PP2A is critical in driving PAH, and BBR may alleviate PAH via PP2A signaling pathways, thereby offering a potential therapeutic option for PAH.

show abstract

PP2A inhibitors induce apoptosis in pancreatic cancer cell line PANC-1 through persistent phosphorylation of IKKα and sustained activation of the NF-κB pathway

Cited by 48 publications

References 44 publications

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac

LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential

Berberine attenuates pulmonary arterial hypertension via protein phosphatase 2A signaling pathway both in vivo and in vitro

Contact Info

Product

Resources

About