Differential effects of Stat3 inhibition in sparse vs confluent normal and breast cancer cells.
The signal transducer and activator of transcription-3 (Stat3) is persistently activated in many cancers such as cancer of the breast and is required for transformation by a number of oncogenes. Signaling through Stat3 is determined by a key phosphorylation at tyr-705. We previously demonstrated that cell-to-cell adhesion brought about through cell aggregation or confluence of cultured cells causes a dramatic increase in Stat3 tyr705 phosphorylation and consequently Stat3 activity in both normal and tumor cells. To examine the role of Stat3 at specific time-points relative to confluence, we used two different approaches of Stat3 inhibition: (1). Introduction of high levels of peptide analogues, which block the Stat3-SH2 domain, to inhibit Stat3 binding to and phosphorylation by growth factor receptors. (2). Treatment with two platinum compounds which bind the Stat3 protein and inhibit its activity without affecting its phosphorylation directly. The results demonstrate that Stat3 downregulation in vSrc transformed NIH3T3 cells or in breast cancer lines harboring activated Src induces apoptosis, which is evident at all densities but is more pronounced at post-confluence. In normal cells on the other hand, Stat3 inhibition at post-confluence caused apoptosis while in sparsely growing cells it induced merely a growth retardation.
Anagnostopoulou
Aikaterini
A
Department of Microbiology, Queen's University, Kingston, Ont., Canada K7L3N6.
Vultur
Adina
A
Arulanandam
Rozanne
R
Cao
Jun
J
Turkson
James
J
Jove
Richard
R
Kim
Joon S
JS
Glenn
Matthew
M
Hamilton
Andrew D
AD
Raptis
Leda
L
D000818:Animals; D017209:Apoptosis; D001940:Breast / Q000166:cytology* / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D018929:Cell Culture Techniques / Q000379:methods*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured / Q000187:drug effects; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D018909:src Homology Domains; D019061:src-Family Kinases / Q000502:physiology*
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019061:src-Family Kinases