Carnosic acid modulates Akt/IKK/NF-κB signaling by PP2A and induces intrinsic and extrinsic pathway mediated apoptosis in human prostate carcinoma PC-3 cells

• Published in: Apoptosis (London) Vol. 17; no. 7; pp. 735 - 747
• Main Authors: Kar, Susanta, Palit, Shreyasi, Ball, Writoban Basu, Das, Pijush K.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.07.2012
• Subjects: Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Biology; Cell Line, Tumor; Cell Proliferation - drug effects; Diterpenes, Abietane - pharmacology; Down-Regulation - drug effects; Drug Screening Assays, Antitumor; Enzyme Activation - drug effects; Humans; I-kappa B Kinase - metabolism; Male; NF-kappa B - metabolism; Oncology; Original Paper; Plant Extracts - pharmacology; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - pathology; Protein Phosphatase 2 - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Virology; NF-κB; PP2A; Akt; Prostate cancer; Carnosic acid
• ISSN: 1360-8185; 1573-675X; 1573-675X
• DOI: 10.1007/s10495-012-0715-4

This study investigates the efficacy of carnosic acid (CA), a polyphenolic diterpene, isolated from the plant rosemary ( Rosemarinus officinalis ), on androgen-independent human prostate cancer PC-3 cells. CA induced anti-proliferative effects in PC-3 cells in a concentration- and time-dependent manner, which was due to apoptotic induction as evident from flow-cytometry, DNA laddering and TUNEL assay. Apoptosis was associated with the activation of caspase-8, -9, -3 and -7, increase in Bax:Bcl-2 ratio, release of cytochrome-c and decrease in expression of inhibitor of apoptosis (IAP) family of proteins. Apoptosis was attenuated upon pretreatment with specific inhibitors of caspase-8 (Z-IETD-fmk) and caspase-9 (Z-LEHD-fmk) suggesting the involvement of both intrinsic and extrinsic apoptotic cascades. Further, apoptosis resulted from the inhibition of IKK/NF-κB pathway as evident from decreased DNA binding activity, nuclear translocation of p50 and p65 and IκBα phosphorylation. The down-regulation of IKK/NF-κB was associated with inhibition of Akt phosphorylation and its kinase activity with a concomitant increase in the serine/threonine protein phosphatase 2A (PP2A) activity. Pharmacologic inhibition of PP2A by okadaic acid and calyculin A, significantly reversed CA-mediated apoptotic events in PC-3 cells indicating that CA induced apoptosis by activation of PP2A through modulation of Akt/IKK/NF-κB pathway. In addition, CA induced apoptosis in another androgen refractory prostate cancer DU145 cells via intrinsic pathway as evidenced from the activation of caspase 3, cleavage of PARP, increase in Bax:Bcl-2 ratio and cytochrome-c release. Carnosic acid, therefore, may have the potential for use in the prevention and/or treatment of prostate cancer.