Rapamycin inhibits lung metastasis of B16 melanoma cells through down-regulating alphav integrin expression and up-regulating apoptosis signaling.
Currently available data indicate the potential application of rapamycin and its analogues in the clinic as anticancer therapeutic agents through inhibiting tumor cell growth and tumor angiogenesis. However, whether rapamycin can directly suppress tumor metastasis remains unclear. In the present study, we demonstrated that rapamycin treatment results in reduced formation of metastatic nodules in the lung by B16 cells. This is due to two mechanisms. First, the expression of alphav integrin is down-regulated by rapamycin treatment, and subsequently, the phosphorylation of focal adhesion kinase (FAK) is reduced. Second, rapamycin promotes apoptosis by up-regulating the proapoptotic molecules Bid and Bax and down-regulating Bcl-xL. Blocking the apoptosis pathway by pan-caspase inhibitor zVAD partially reversed the suppression of rapamycin in B16 metastasis. Interestingly, rapamycin up-regulates Bax and Bid in B16 cells via the S6K1 pathway and down-regulates the expression of alphav integrin via other pathway(s). In addition, our data showed that autophagy was not involved in the mechanisms of rapamycin-mediated metastasis suppression. Our findings demonstrate a potential anti-metastatic effect of rapamycin via down-regulating alphav integrin expression and up-regulating apoptosis signaling, suggesting that rapamycin might be worthy of clinical evaluation as an antimetastatic agent.
Yang
Zhuoshun
Z
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Lei
Zhang
Z
Li
Bo
B
Zhou
Yu
Y
Zhang
Gui-Mei
GM
Feng
Zuo-Hua
ZH
Zhang
Biao
B
Shen
Guan-Xin
GX
Huang
Bo
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D039564:Integrin alphaV / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
D039564:Integrin alphaV; D047908:Intracellular Signaling Peptides and Proteins; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus