Bacterial N-acylhomoserine lactone-induced apoptosis in breast carcinoma cells correlated with down-modulation of STAT3

Abstract

Cell growth is promoted by mitogens and survival factors, which activate intracellular signalling pathways to control cell cycle progression and cellular integrity. Proliferation signals are transmitted through Ras and Rho family small G-proteins coupled to mitogen-activated protein kinase (MAPK) cascades, while survival signals are propagated by lipid-dependent kinases such as phosphatidylinositide 3-kinases (PI3Ks) and protein kinase B (Akt/PKB). Recently, signal transducer and activator of transcription (STAT) proteins were identified as positive regulators of proliferation in a variety of cell types. Persistent activation of these pathways is associated with tumour cell growth, whereas their inhibition can halt proliferation and precipitate apoptotic cell death. The human pathogen Pseudomonas aeruginosa uses quorum-sensing signal molecules (QSSMs) to regulate virulence gene expression. QSSMs also suppress host immune responses although the mechanism of suppression is unknown. Here, we demonstrate that the QSSM N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) from P. aeruginosa blocks proliferation and induces apoptosis in human BC cell lines. Analyses of signalling events reveal that OdDHL has little or no effect on MAPK cascades, partially inhibits the Akt/PKB pathway and ablates STAT3 activity. Pharmacological inhibition of each pathway independently indicates that STAT3 activity is critical for BC cell proliferation and survival, while a constitutively active STAT3 confers resistance to OdDHL. These results support the notion of OdDHL as a bioactive molecule in eukaryotic systems and a paradigm for a novel class of antiproliferative compounds.

N-(3-Oxo-acyl)homoserine Lactones Signal Cell Activation through a Mechanism distinct from the Canonical Pathogen-associated Molecular Pattern Recognition Receptor Pathways

“…This assumption is consistent with observations by others that C12 inhibits cell proliferation (22,23).…”

“…The abilities of this Gram-negative bacterium to survive and establish chronic infections in the host appear to be associated with functions of C12 (20,21). Interestingly, C12 has also been reported to exhibit effects on eukaryotic cells (15,21) including inhibition of cell proliferation (22,23), induction of apoptosis (23,24), and nuclear translocation of NF-B (15,25). These observations suggest that C12 may function as a PAMP.…”

Nasal chemosensory cells use bitter taste signaling to detect irritants and bacterial signals

“…40). For example, AHLs can influence inflammatory responses (41)(42)(43), chemotaxis (44), induction of apoptosis (45)(46)(47), and mucus secretion (10). All of these responses are relatively slow and involve changes in gene regulatory networks or secretory mechanisms.…”

Modulation of Gene Expression and Tumor Cell Growth by Redox Modification of STAT3

“…Intriguingly, STAT3 inhibition can be achieved by lowering (via antioxidants) or raising sufficiently the intracellular oxidative potential (19). Moreover, inhibition of STAT3 by other means has been shown to induce apoptosis (43,44). This correlation implies that the adverse effects of peroxide are manifested when STAT3 activity is compromised.…”