Beta-sitosterol-induced-apoptosis is mediated by the activation of ERK and the downregulation of Akt in MCA-102 murine fibrosarcoma cells.
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.
Moon
Dong-Oh
DO
Faculty of Applied Marine Science, Cheju National University, Jeju-si, Jeju Special Self-Governing Province 690-756, South Korea.
Lee
Kyeong-Jun
KJ
Choi
Yung Hyun
YH
Kim
Gi-Young
GY
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005354:Fibrosarcoma / Q000378:metabolism / Q000473:pathology; D016193:G1 Phase / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D012855:Sitosterols / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000873:Anthracenes; D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D020169:Caspases; D002867:Chromones; D048049:Extracellular Signal-Regulated MAP Kinases; D000960:Hypolipidemic Agents; D007093:Imidazoles; D009025:Morpholines; D009842:Oligopeptides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D012855:Sitosterols; D016159:Tumor Suppressor Protein p53; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C052617:Bcl2 protein, mouse; C432165:pyrazolanthrone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C025473:gamma-sitosterol; C514862:Akt1 protein, mouse; C093642:SB 203580