Isosilybin A induces apoptosis in human prostate cancer cells via targeting Akt, NF-κB, and androgen receptor signaling.
Prostate cancer (PCA) is the second most malignancy in American men. Advanced stage PCA cells possess unlimited replication potential as well as resistance to apoptosis. Therefore, targeting survival mechanisms and activating apoptotic machinery in PCA cells using nontoxic phytochemicals is suggested as an attractive strategy against this deadly malignancy. In the present study, we assessed the effect of one such botanical agent, namely isosilybin A, on apoptotic machinery and key members of cell survival signaling [Akt, NF-κB, and androgen receptor (AR)] in different PCA cells. Results showed that isosilybin A (90-180 µM) treatment significantly induces apoptotic death by activating both extrinsic (increased level of DR5 and cleaved caspase 8) and intrinsic pathways (caspase 9 and 3 activation) of apoptosis in three different human PCA cell lines namely 22Rv1, LAPC4, and LNCaP. Further, isosilybin A treatment decreased the levels of phospho-Akt (serine-473), total Akt, and the nuclear levels of NF-κB constituents (p50 and p65). Isosilybin A treatment also decreased the AR and PSA level in 22Rv1, LAPC4, and LNCaP cells. Employing pan-caspase inhibitor (Z-VAD.fmk), we confirmed that isosilybin A-mediated decreased AR is independent of caspases activation. Temporal kinetics analysis showed that the primary effect of isosilybin A is on AR, as decrease in AR was evident much earlier (4 h) relative to caspase activation and apoptosis induction (12 h). Overall, our results demonstrated that isosilybin A activates apoptotic machinery in PCA cells via targeting Akt-NF-κB-AR axis; thereby, indicating a promising role for this phytochemical in the management of clinical PCA.
Deep
Gagan
G
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Aurora, Colorado, USA.
Gangar
Subhash C
SC
Oberlies
Nicholas H
NH
Kroll
David J
DJ
Agarwal
Rajesh
R
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D012838:Silymarin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
C410798:AR protein, human; D000972:Antineoplastic Agents, Phytogenic; D016328:NF-kappa B; D011944:Receptors, Androgen; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D012838:Silymarin; D051996:Transcription Factor RelA; D051057:Proto-Oncogene Proteins c-akt; D053181:Caspase 8; C523198:isosilybin A