Farnesol inhibits tumor growth and enhances the anticancer effects of bortezomib in multiple myeloma xenograft mouse model through the modulation of STAT3 signaling pathway

被引:121
|
作者
Lee, Jong Hyun [1 ]
Kim, Chulwon [1 ]
Kim, Sung-Hoon [1 ]
Sethi, Gautam [2 ]
Ahn, Kwang Seok [1 ]
机构
[1] Kyung Hee Univ, Coll Korean Med, Seoul 130701, South Korea
[2] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore 117597, Singapore
关键词
Farnesol; STAT3; Multiple myeloma; Apoptosis; ISOPRENOID-MEDIATED INHIBITION; CONSTITUTIVE ACTIVATION; PANCREATIC-CANCER; PPAR-ALPHA; MEVALONATE SYNTHESIS; DIETARY ISOPRENOIDS; MOLECULAR TARGETS; PERILLYL ALCOHOL; BREAST-CANCER; APOPTOSIS;
D O I
10.1016/j.canlet.2015.02.024
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 famesol (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 downregulation 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 (Bar) 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. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:280 / 293
页数:14
相关论文
共 50 条
  • [31] Artesunate suppresses tumor growth and induces apoptosis through the modulation of multiple oncogenic cascades in a chronic myeloid leukemia xenograft mouse model
    Kim, Chulwon
    Lee, Jong Hyun
    Kim, Sung-Hoon
    Sethi, Gautam
    Ahn, Kwang Seok
    ONCOTARGET, 2015, 6 (06) : 4020 - 4035
  • [32] Luteolin inhibits diffuse large B-cell lymphoma cell growth through the JAK2/STAT3 signaling pathway
    Zhan, Xin-Zhuo
    Bo, Yi-Wen
    Zhang, Yu
    Zhang, Hai-Dong
    Shang, Zhi-Hao
    Yu, Hui
    Chen, Xiao-Li
    Kong, Xiang-Tu
    Zhao, Wan-Zhou
    Teimonen, Timo
    Liu, Tao
    Lu, Meng-Yi
    Yang, Ye
    Sun, Shan-Liang
    Ni, Hai-Wen
    FRONTIERS IN PHARMACOLOGY, 2025, 16
  • [33] A Flavone from Traditional East Asian Natural Extract Inhibits STAT3 and Tumor Growth in a Syngeneic Mouse Breast Cancer Model
    Senthil, M.
    Akmal, Y. M.
    Xing, Q.
    Yan, J.
    Yim, J. H.
    CANCER RESEARCH, 2010, 70
  • [34] Pien Tze Huang inhibits tumor cell proliferation and promotes apoptosis via suppressing the STAT3 pathway in a colorectal cancer mouse model
    Zhuang, Qunchuan
    Hong, Fei
    Shen, Aling
    Zheng, Liangpu
    Zeng, Jianwei
    Lin, Wei
    Chen, Youqin
    Sferra, Thomas J.
    Hong, Zhenfeng
    Peng, Jun
    INTERNATIONAL JOURNAL OF ONCOLOGY, 2012, 40 (05) : 1569 - 1574
  • [35] Dietary Curcumin Attenuates Glioma Growth in a Syngeneic Mouse Model by Inhibition of the JAK1,2/STAT3 Signaling Pathway
    Weissenberger, Jakob
    Priester, Maike
    Bernreuther, Christian
    Rakel, Stefanie
    Glatzel, Markus
    Seifert, Volker
    Koegel, Donat
    CLINICAL CANCER RESEARCH, 2010, 16 (23) : 5781 - 5795
  • [36] STAT3/NF-κB decoy oligodeoxynucleotides inhibit atherosclerosis through regulation of the STAT/NF-κB signaling pathway in a mouse model of atherosclerosis
    An, Hyun-Jin
    Gwon, Mi-Gyeong
    Gu, Hyemin
    Bae, Seongjae
    Leem, Jaechan
    Lee, Jin Bae
    Park, Kwan-Kyu
    INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, 2023, 51 (05)
  • [37] Phosphorylated STAT3 reflects anti-tumor activity of anti-IL-6 therapy in a mouse model of multiple myeloma.
    Hanson, R
    McCabe, F
    Zaki, M
    Nemeth, JA
    CLINICAL CANCER RESEARCH, 2005, 11 (24) : 8982S - 8983S
  • [38] Lachnochromonin, a fungal metabolite from Lachnum virgineum, inhibits cell growth and promotes apoptosis in tumor cells through JAK/ STAT3 signaling
    Chu, Jun
    Zhai, Wanli
    Geng, Yongtao
    Feng, Yarui
    Wang, Jiayu
    Li, Jun
    Wang, Yinyin
    Zhuang, Wenying
    Che, Yongsheng
    Li, Yi
    Chang, Zhijie
    Ren, Fangli
    CELLULAR SIGNALLING, 2023, 106
  • [39] Tanreqing injection inhibits stemness and enhances sensitivity of non-small cell lung cancer models to gefitinib through ROS/STAT3 signaling pathway
    Xiao, Zhenzhen
    Ding, Lina
    Yu, Yaya
    Ma, Changju
    Lei, Chenjing
    Liu, Yihong
    Chang, Xuesong
    Chen, Yadong
    He, Yihan
    Zhu, Yanjuan
    Zhang, Haibo
    JOURNAL OF CANCER, 2024, 15 (13): : 4259 - 4274
  • [40] Resveratrol inhibits STAT3 signaling pathway through the induction of SOCS-1: Role in apoptosis induction and radiosensitization in head and neck tumor cells
    Baek, Seung Ho
    Ko, Jeong-Hyeon
    Lee, Hanwool
    Jung, Jinhong
    Kong, Moonkyoo
    Lee, Jung-Woo
    Lee, Junhee
    Chinnathambi, Arunachalam
    Zayed, M. E.
    Alharbi, Sulaiman Ali
    Lee, Seok-Geun
    Shim, Bum Sang
    Sethi, Gautam
    Kim, Sung-Hoon
    Yang, Woong Mo
    Um, Jae-Young
    Ahn, Kwang Seok
    PHYTOMEDICINE, 2016, 23 (05) : 566 - 577