title: Ursolic acid inhibits multiple cell survival pathways leading to suppression of growth of prostate cancer xenograft in nude mice.
abstract: Activation of transcription factors nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) is frequently observed in prostate cancer and has been linked with tumor cell proliferation, invasion, metastasis, and angiogenesis. In this study, we investigated the effect of ursolic acid (UA) on NF-κB and STAT3 signaling pathways in both androgen-independent (DU145) and androgen-dependent (LNCaP) prostate cancer cell lines and also prospectively tested the hypothesis of NF-κB and STAT3 inhibition using a virtual predictive functional proteomics tumor pathway technology platform. We found that UA inhibited constitutive and TNF-α-induced activation of NF-κB in DU145 and LNCaP cells in a dose-dependent manner. The suppression was mediated through the inhibition of constitutive and TNF-α-induced IκB kinase (IKK) activation, phosphorylation of IκBα and p65 and NF-κB-dependent reporter activity. Furthermore, UA suppressed both constitutive and inducible STAT3 activation in prostate cancer cells concomitant with suppression of activation of upstream kinases (Src and JAK2) and STAT3-dependent reporter gene activity. UA also downregulated the expression of various NF-κB and STAT3 regulated gene products involved in proliferation, survival, and angiogenesis and induced apoptosis in both cells lines as evidenced by DNA fragmentation and annexin V staining. In vivo, UA (200 mg/kg b.w.) treated for 6 weeks inhibited the growth of DU145 cells in nude mice without any significant effect on body weight. Overall, our results from experimental and predictive studies suggest that UA mediates its anti-tumor effects through suppression of NF-κB and STAT3 pathways in prostate cancer.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore.
authors.forename: Muthu K
authors.initials: MK
authors.lastname: Shanmugam
authors.forename: Peramaiyan
authors.initials: P
authors.lastname: Rajendran
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Tarang
authors.initials: T
authors.lastname: Nema
authors.forename: Shireen
authors.initials: S
authors.lastname: Vali
authors.forename: Taher
authors.initials: T
authors.lastname: Abbasi
authors.forename: Shweta
authors.initials: S
authors.lastname: Kapoor
authors.forename: Ashish
authors.initials: A
authors.lastname: Sharma
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.forename: Paul C
authors.initials: PC
authors.lastname: Ho
authors.forename: Kam M
authors.initials: KM
authors.lastname: Hui
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014315:Triterpenes / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D019892:eIF-2 Kinase / Q000378:metabolism; D000097245:Ursolic Acid; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051550:I-kappa B Kinase; D015850:Interleukin-6; D053614:Janus Kinase 2; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D050796:STAT3 Transcription Factor; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; D019892:eIF-2 Kinase; D000097245:Ursolic Acid; D000097782:NF-kappaB-Inducing Kinase