期刊
INTERNATIONAL IMMUNOPHARMACOLOGY
卷 7, 期 8, 页码 1044-1053出版社
ELSEVIER
DOI: 10.1016/j.intimp.2007.03.010
关键词
beta-Sitosterol; Mitogen-activated protein kinase; extracellular-signal regulating kinase; c-Jun N-terminal kinase; PI3K/Akt
beta-Sitosterol (SITO) is a potential candidate for cancer chemotherapy, however, little is known about the cellular and molecular mechanisms in cancer cells. We herein identified how SITO induces anti-proliferation and cell death in MCA-102 fibrosarcoma cells. SITO exposure induced-apoptosis and the cell death resulted from a significant loss of the Bcl-2 and the inhibitor of apoptosis protein (IAP) family (XIAP, cIAP-1 and cIAP-2), and increased Bax with an alteration of p53 and p21. SITO-induced cell death significantly also increased caspase activity and poly(ADP-ribose) polymerase (PARP) cleavage, and caspase-3 inhibitor z-DEVD-fmk significantly inhibited SITO-induced cell death. These data suggest that the activation of caspase-3 is associated with SITO-induced-apoptosis. Treatment with SITO also induced phosphorylation of extracellular-signal regulating kinase (ERK) and p38 mitogen-activated protein kinase (MARK), but not c-Jun N-terminal kinase (JNK). A specific ERK inhibitor PD98059 significantly blocks SITO-induced-apoptosis, whereas a JNK inhibitor SP600125 has no affect. A p38 MAPK inhibitor SB203580 very slightly suppressed cell death. The induction of apoptosis was also accompanied by an inactivation of phosphatidylinositol 3-kinase (PI3K)/ Akt, and PI3K inhibitor LY29004 significantly increases SITO-induced cell death. These findings provide evidence demonstrating that the proapoptotic effect of SITO is mediated through the activation of ERK and the block of the PI3K/Akt signal pathway in MCA-102 cells. Therefore, SITO has a strong potential as a therapeutic agent for preventing cancers such as fibrosarcoma. (C) 2007 Published by Elsevier B.V.
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