Carnosol induces apoptosis through generation of ROS and inactivation of STAT3 signaling in human colon cancer HCT116 cells

• Published in: International journal of oncology Vol. 44; no. 4; pp. 1309 - 1315
• Main Authors: PARK, KI-WOONG, KUNDU, JUTHIKA, CHAE, IN-GYEONG, KIM, DO-HEE, YU, MI-HEE, KUNDU, JOYDEB KUMAR, CHUN, KYUNG-SOO
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.04.2014; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; bcl-2-Associated X Protein - biosynthesis; bcl-X Protein - biosynthesis; Cancer; Care and treatment; carnosol; Caspase 3 - biosynthesis; Caspase 9 - biosynthesis; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Colon cancer; Colonic Neoplasms - drug therapy; Colorectal cancer; Cyclin D1 - biosynthesis; Cyclin D2 - biosynthesis; Cyclin D3 - biosynthesis; Diterpenes, Abietane - pharmacology; DNA-Binding Proteins; Genes; HCT116 Cells; Health aspects; Humans; Inhibitor of Apoptosis Proteins - biosynthesis; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - metabolism; Kinases; Materia medica, Vegetable; Oncology, Experimental; p53; Phosphorylation; Plant extracts; Poly(ADP-ribose) Polymerases - metabolism; Proteins; Proto-Oncogene Proteins c-mdm2 - biosynthesis; Reactive oxygen species; Reactive Oxygen Species - metabolism; Rodents; Rosemary; signal transducer and activator of transcription-3; Signal Transduction - drug effects; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; STAT3 Transcription Factor - antagonists & inhibitors; Tumor Suppressor Protein p53 - biosynthesis; Tumors; United States > US
• DOI: 10.3892/ijo.2014.2281
• ISSN: 1019-6439

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.