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

Abstract

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.

Lipopolysaccharide (LPS) enhances prostate cancer metastasis potentially through NF‐κB activation and recurrent dexamethasone administration fails to suppress it in vivo

“…We believe that, this effect could be through both direct and indirect methods of LPS-mediated NF-κB activation in PCa cells. 18,24,25,62,63 No metastasis was observed in our DU145 orthotopic tumor model that confirms previously reported less metastatic nature of these cells. 64 Similarly, it also indicates that only NF-κB activation in these cells by an exogenous stimulus (here LPS) might not significantly alter the intrinsic metastatic property of these cells.…”

“…Despite certain unexpected results, our in vivo study has for the first‐time provided the evidence that systemic administration of LPS could activate NF‐κB in PCa cells (Figures A and B) and enhance PCa cells metastasis in a cell line dependent manner (Figure A). We believe that, this effect could be through both direct and indirect methods of LPS‐mediated NF‐κB activation in PCa cells . No metastasis was observed in our DU145 orthotopic tumor model that confirms previously reported less metastatic nature of these cells .…”

Role of tumor microenvironment in tumorigenesis

“…Several studies in mice have revealed that the depletion of macrophages during tumor induction restrained tumor growth 91, 92. Regarding the escape stage, the immune system may help tumor cells to format the clinical characterization of tumor immune escape mechanisms, while many experiments have proven that immune cells can reduce anti-cancer proteins or cytokines to promote cancer invasion 93, 94. In addition, one experiment also found that immune cells may be related to the regulation of apoptosis 95.…”

Neutrophil/lymphocyte ratio is a more sensitive systemic inflammatory response biomarker than platelet/lymphocyte ratio in the prognosis evaluation of unresectable pancreatic cancer

“…Even for those who received surgery, they might finally suffer from recurrence or metastasis. Chemotherapy is still one of the major treatments for pancreatic cancer [ 1 ] [ 2 ] [ 3 ].…”