title: Farnesol inhibits tumor growth and enhances the anticancer effects of bortezomib in multiple myeloma xenograft mouse model through the modulation of STAT3 signaling pathway.
abstract: Aberrant activation of signal transducer and activator of transcription 3 (STAT3) is frequently observed in multiple myeloma (MM) cancer and can upregulate the expression of several genes involved in proliferation, survival, metastasis, and angiogenesis. The effect of farnesol (FOH) on STAT3 activation, associated protein kinases, its regulated gene products, cellular proliferation, and apoptosis was examined. The in vivo effect of FOH on the growth of human MM xenograft tumors alone and in combination with bortezomib (Bor) in athymic nu/nu female mice was also investigated. We found that FOH suppressed both constitutive and inducible STAT3 activation at Tyr705 in MM cells. The suppression of STAT3 was mediated through the inhibition of activation of upstream JAK1, JAK2, and c-Src kinases. Also, treatment with the protein tyrosine phosphatase (PTP) inhibitor, pervanadate treatment reversed the FOH-induced down-regulation of STAT3, possibly indicating the involvement of a PTP. Indeed, we found that FOH treatment induces the increased expression of SHP-2 protein and knockdown of the SHP-2 gene by small interfering RNA suppressed the ability of FOH to inhibit STAT3 activation. FOH inhibited proliferation and significantly potentiated the apoptotic effects of bortezomib (Bor) in U266 cells. When administered intraperitoneally, FOH enhanced Bor-induced growth suppression of human MM xenograft tumors in athymic nu/nu female mice. Our results suggest that FOH is a novel blocker of STAT3 signaling pathway and exerts both anti-proliferative and apoptotic activities in MM in vitro and in vivo.
authors.affiliation: College of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, Seoul 130-701, South Korea.
authors.forename: Jong Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: College of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, Seoul 130-701, South Korea.
authors.forename: Chulwon
authors.initials: C
authors.lastname: Kim
authors.affiliation: College of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, Seoul 130-701, South Korea.
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597. Electronic address: phcgs@nus.edu.sg.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.affiliation: College of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, Seoul 130-701, South Korea. Electronic address: ksahn@khu.ac.kr.
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005204:Farnesol / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D005204:Farnesol; D000069286:Bortezomib
keywords: Apoptosis; Farnesol; Multiple myeloma; STAT3