Carnosol induces apoptosis through generation of ROS and inactivation of STAT3 signaling in human colon cancer HCT116 cells.
Carnosol, an active constituent of rosemary, has been reported to possess anti-inflammatory and anticancer activities. However, the molecular mechanisms underlying the anticancer effects of carnosol remain poorly understood. In the present study, we found that carnosol significantly reduced the viability of human colon cancer (HCT116) cells in a concentration- and time-dependent manner. Treatment of cells with carnosol induced apoptosis, which was associated with activation of caspase-9 and -3 and the cleavage of poly-(ADP-ribose) polymerase (PARP). Incubation with carnosol elevated the expression of Bax and inhibited the levels of Bcl-2 and Bcl-xl. Carnosol induced expression of p53 and inhibited that of murine-double minute-2 (Mdm2). Moreover, carnosol generated reactive oxygen species (ROS), and pretreatment with N-acetyl cysteine abrogated carnosol-induced cleavage of caspase-3 and PARP. The constitutive phosphorylation, the DNA binding and reporter gene activity of signal transducer and activator of transcription-3 (STAT3) was diminished by treatment with carnosol. To further elucidate the molecular mechanisms of STAT3 inactivation, we found that carnosol attenuated the phosphorylation of Janus-activated kinase-2 (Jak2) and Src kinase. Pharmacological inhibition of Jak2 and Src inhibited STAT3 phosphorylation. Furthermore, carnosol attenuated the expression of STAT3 target gene products, such as survivin, cyclin-D1, -D2, and -D3. Taken together, our study provides the first report that carnosol induced apoptosis in HCT116 cells via generation of ROS, induction of p53, activation of caspases and inhibition of STAT3 signaling pathway.
College of Pharmacy, Keimyung University, Daegu 704-701, Republic of Korea.
Ki-Woong
KW
Park
College of Pharmacy, Keimyung University, Daegu 704-701, Republic of Korea.
Juthika
J
Kundu
College of Pharmacy, Keimyung University, Daegu 704-701, Republic of Korea.
In-Gyeong
IG
Chae
College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
Do-Hee
DH
Kim
Department of Food Science and Technology, Keimyung University, Daegu 704-701, Republic of Korea.
Mi-Hee
MH
Yu
College of Pharmacy, Keimyung University, Daegu 704-701, Republic of Korea.
Joydeb Kumar
JK
Kundu
College of Pharmacy, Keimyung University, Daegu 704-701, Republic of Korea.
Kyung-Soo
KS
Chun
D045784:Abietanes / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000096:biosynthesis; D053453:Caspase 9 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy*; D019938:Cyclin D1 / Q000096:biosynthesis; D056742:Cyclin D2 / Q000096:biosynthesis; D056743:Cyclin D3 / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D045325:HCT116 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis; D051020:bcl-X Protein / Q000096:biosynthesis; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D045784:Abietanes; D000970:Antineoplastic Agents; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C107489:BIRC5 protein, human; C080336:CCND2 protein, human; C534696:CCND3 protein, human; D056742:Cyclin D2; D056743:Cyclin D3; D004268:DNA-Binding Proteins; D051034:Inhibitor of Apoptosis Proteins; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019938:Cyclin D1; C068623:carnosol; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D011065:Poly(ADP-ribose) Polymerases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D019061:src-Family Kinases; D053148:Caspase 3; D053453:Caspase 9