Bacteria peptidoglycan promoted breast cancer cell invasiveness and adhesiveness by targeting toll-like receptor 2 in the cancer cells.
Chronic bacterial infection increased the risk of many solid malignancies and the underlying mechanism is usually ascribed to bacterial-caused inflammation. However, the direct interaction of infectious bacteria with cancer cells has been largely overlooked. We identified that highly metastatic breast cancer MDA-MB-231 cells expressed high level of Toll-like receptor 2 (TLR2) in contrast to poorly metastatic breast cancer cells and homogenous untransformed breast cells. TLR2 in MDA-MB-231 cells were actively triggered by peptidoglycan (PGN) from infectious bacterium Staphylococcus aureus (PGN-SA), resulting in the promoted invasiveness and adhesiveness of the cancer cells in vitro. PGN-SA induced phosphorylation of TAK1 and IkappaB in the TLR2-NF-kappaB pathway of the cancer cells and stimulated IL-6 and TGF-beta secretion in MDA-MB-231 cells. All these effects were abrogated by TLR2 blockade. Further investigation showed that the NF-kappaB, STAT3 and Smad3 activities were augmented sequentially in MDA-MB-231 cells after PGN-SA stimulation. Phosphorylation of NF-kappaBp65 was initially increased and then followed by phosphorylation of STAT3 and Smad3 in the delayed 4 or 6 hours. NF-kappaB inhibition attenuated STAT3 and Smad3 activities whereas PGN-SA-stimulated cell culture supernatants reversed these inhibitory effects. Our study indicated that TLR2 activation by infectious bacterial PGN played an important role in breast cancer cell invasiveness and illustrated a new link between infectious bacteria and the cancer cells, suggesting the importance of antibiotic therapy to treat cancer with bacterial infection.
Biology Research Institute of the United Laboratories International Holdings Limited, Zhuhai, China. xiewj75@126.com
Wenjie
W
Xie
Yafang
Y
Huang
Wenling
W
Xie
Aimin
A
Guo
Wei
W
Wu
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010457:Peptidoglycan / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism; D013211:Staphylococcus aureus / Q000737:chemistry*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D015850:Interleukin-6; D016328:NF-kappa B; D010457:Peptidoglycan; C497790:SMAD3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051900:Smad3 Protein; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D016212:Transforming Growth Factor beta