The marine natural product microsclerodermin A is a novel inhibitor of the nuclear factor kappa B and induces apoptosis in pancreatic cancer cells

Abstract

Pancreatic cancer, the 4th leading cause of cancer death in the US, is highly resistant to all current chemotherapies, and its growth is facilitated by chronic inflammation. An important mediator of inflammation is the nuclear factor kappa B (NFκB), a transcription factor that regulates over 500 genes including the regulation of anti-apoptotic proteins, cell cycle progression and cytokine production. NFκB is constitutively activated in pancreatic cancer cells contributing to their resistance to apoptosis and high metastatic potential. Although many small molecules that inhibit NFκB have been identified, none are currently used in the clinic, perhaps due to their lack of specificity. To identify novel inhibitors of NFκB, the HBOI library of enriched fractions from marine organisms was screened using a reporter cell line that produces luciferin under the transcriptional control of NFκB. Fractions from the sponge Amphibleptula were active in this screen and contained the antifungal cyclic peptide microsclerodermin A. Microsclerodermin A is shown here to inhibit NFκB transcriptional activity in a reporter cell line, to reduce levels of phosphorylated (active) NFκB in the AsPC-1 cell line, to have an IC50 for cytotoxicity in the low micromolar range against the AsPC-1, BxPC-3, MIA PaCa-2 and PANC-1 pancreatic cancer cell lines, and to induce significant apoptosis in the AsPC-1, BxPC-3 and the PANC-1 cell lines. Treatment of AsPC-1 cells with microsclerodermin A also resulted in an increase in IL-8 production without apparent induction of angiogenic factors and there is the possibility that inhibition of NFκB by microsclerodermin A is mediated by the glycogen synthase kinase 3β pathway.

SERP1 is a novel marker of poor prognosis in pancreatic ductal adenocarcinoma patients via anti-apoptosis and regulating SRPRB/NF-κB axis

“…SERP1 downregulation promoted cell apoptosis via upregulating apoptosis-related protein SRP receptor β subunit (SRPRB) expression and inhibiting nuclear factor-κB (NF-κB) activation. Previous studies have verified that NF-κB is a known regulator of anti-apoptotic molecules ( 13 , 14 ), is constitutively activated by phosphorylation modification in various tumors including PDAC ( 15 – 17 ). NF-κB phosphorylation exist in PDAC cells such as PANC-1, BxPC-3 and AsPC-1, and contributing to their resistance to apoptosis and high metastatic potential ( 14 ).…”

The cnidarian origin of the proto-oncogenes NF-κB/STAT and WNT-like oncogenic pathway drives the ctenophores (Review)

“…Dexamethasone, pyrrolidine dithio-carbamate, BAY-11-7082; the sponge-derivative marine natural product microsclerodermin inhibit or alter the excretions of inflammatory chemokines (CXCL8/10) and interleukins (IL-1β, IL-6 and IL-8), but have not been enlisted as effective anticancer agents ( 59 – 61 ). Anti-NF-κB RNA-aptamers (specifically target-binding short ss nucleotides) and siRNAs are powerful NF-κB inhibitors ( 62 ), not yet in clinical use.…”

“…The Hh/Gli and the Wnt/β-catenin pathways appear in combination ( 132 ). The sponge Amphimedon releases the antifungal cyclic peptide microsclerodermin ( 61 ). NF-κB is constitutively activated in pancreatic adenocarcinoma cells.…”

“…NF-κB is constitutively activated in pancreatic adenocarcinoma cells. Microsclerodermin blocked NF-κB production in pancreatic adenocarcinoma cells and forced cell death in the form of apoptosis ( 61 ). In the Wnt pathway, β-catenin and DNA methyltransferase (DNMT) co-localize in tumor cell nuclei.…”

NO-Donor Nitrosyl Iron Complex with 2-Aminophenolyl Ligand Induces Apoptosis and Inhibits NF-κB Function in HeLa Cells

“…NF-κB signaling is well recognized as an important molecular crossway that contributes to various diseases, including cancer [67][68][69][70][71][72][73]. Chemical compounds that inhibit NF-κB, either directly or via its upstream regulators, cause cell death and suppress tumor growth [74][75][76][77][78][79][80][81][82][83] or sensitize cancer cells to radiation or chemotherapeutic agents [84][85][86].…”