title: Carnosic acid induces apoptosis through inactivation of Src/STAT3 signaling pathway in human renal carcinoma Caki cells.
abstract: Carnosic acid (CA), the major bioactive compound of Rosmarinus officinalis L., has been reported to possess anti-inflammatory and anticancer activities. However, the molecular mechanisms underlying the anticancer effects of CA remain poorly understood. In the present study, we investigated that CA significantly reduced the viability of human renal carcinoma Caki cells. CA-induced apoptosis was connected with the cleavage of caspase-9, -7 and -3, and that of PARP. Moreover, CA increased the expression of pro-apoptotic protein Bax and diminished the expression of anti-apoptotic protein Bcl-2 and Bcl-xL, thereby releasing cytochrome c into the cytosol. Treatment with CA in Caki cells also induced the expression of p53 and its target gene product, p27, through down-regulation of Murine double minute-2 (Mdm2). Furthermore, CA generated reactive oxygen species (ROS), and pretreatment with ROS scavenger N-acetyl cysteine (NAC) abrogated CA-induced cleavage of PARP and expression of p53. One of the key oncogenic signals is mediated through signal transducer and activator of transcription-3 (STAT3), which promotes abnormal cell proliferation. Incubation of cells with CA markedly diminished the phosphorylation of STAT3 and its upstream, Src, and reduced the expression of STAT3 responsive gene products, such as D-series of cyclins and survivin. Taken together, the present study revealed that CA induced apoptosis in Caki cells by induction of p53 and suppression of STAT3 signaling.
authors.affiliation: College of Pharmacy, Keimyung University, Daegu 704-701, Republic of Korea.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Park
authors.affiliation: College of Pharmacy, Keimyung University, Daegu 704-701, Republic of Korea.
authors.forename: Byoungduck
authors.initials: B
authors.lastname: Park
authors.affiliation: College of Pharmacy, Keimyung University, Daegu 704-701, Republic of Korea.
authors.forename: In Gyeong
authors.initials: IG
authors.lastname: Chae
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Do-Hee
authors.initials: DH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Keimyung University, Daegu 704-701, Republic of Korea.
authors.forename: Juthika
authors.initials: J
authors.lastname: Kundu
authors.affiliation: College of Pharmacy, Keimyung University, Daegu 704-701, Republic of Korea.
authors.forename: Joydeb Kumar
authors.initials: JK
authors.lastname: Kundu
authors.affiliation: College of Pharmacy, Keimyung University, Daegu 704-701, Republic of Korea.
authors.forename: Kyung-Soo
authors.initials: KS
authors.lastname: Chun
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D045784:Abietanes; D000972:Antineoplastic Agents, Phytogenic; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019061:src-Family Kinases; C018381:salvin