Inhibition of thromboxane synthase induces lung cancer cell death via increasing the nuclear p27.
The role of thromboxane in lung carcinogenesis is not clearly known, though thromboxane B2 (TXB(2)) level is increased and antagonists of thromboxane receptors or TXA2 can induce apoptosis of lung cancer cells. p27, an atypical tumor suppressor, is normally sequestered in the nucleus. The increased nuclear p27 may result in apoptosis of tumor cells. We hypothesize that the inhibition of thromboxane synthase (TXS) induces the death of lung cancer cells and that such inhibition is associated with the nuclear p27 level. Our experiment showed that the inhibition of TXS significantly induced the death or apoptosis in lung cancer cells. The activity of TXS was increased in lung cancer. The nuclear p27 was remarkably reduced in lung cancer tissues. The inhibition of TXS caused the cell death and apoptosis of lung cancer cells, likely via the elevation of the nuclear p27 since the TXS inhibition promoted the nuclear p27 level and the inhibition of p27 by its siRNA recovered the cell death induced by TXS inhibition. Collectively, lung cancer cells produce high levels of TXB(2) but their nuclear p27 is markedly reduced. The inhibition of TXS results in the p27-related induction of cell death in lung cancer cells.
Leung
Kin Chung
KC
Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
Hsin
Michael K Y
MK
Chan
Joey S Y
JS
Yip
Johnson H Y
JH
Li
Mingyue
M
Leung
Billy C S
BC
Mok
Tony S K
TS
Warner
Timothy D
TD
Underwood
Malcolm J
MJ
Chen
George G
GG
D000230:Adenocarcinoma / Q000473:pathology / Q000601:surgery; D017209:Apoptosis / Q000502:physiology; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000601:surgery; D016923:Cell Death; D002455:Cell Division; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology* / Q000601:surgery; D034741:RNA, Small Interfering / Q000235:genetics; D055752:Small Cell Lung Carcinoma / Q000473:pathology / Q000601:surgery; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D014162:Transfection
D034741:RNA, Small Interfering; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013930:Thromboxane-A Synthase