Saikosaponin-d inhibits proliferation by up-regulating autophagy via the CaMKKβ-AMPK-mTOR pathway in ADPKD cells

被引:39
作者
Shi, Weiwei [1 ]
Xu, Dechao [1 ]
Gu, Junhui [1 ]
Xue, Cheng [1 ]
Yang, Bo [1 ]
Fu, Lili [1 ]
Song, Shuwei [1 ]
Liu, Dongmei [1 ]
Zhou, Wei [1 ]
Lv, Jiayi [1 ]
Sun, Ke [1 ]
Chen, Meihan [1 ]
Mei, Changlin [1 ]
机构
[1] Second Mil Med Univ, Kidney Inst PLA, Dept Nephrol, Changzheng Hosp, 415 Fengyang Rd, Shanghai 200003, Peoples R China
基金
中国博士后科学基金; 中国国家自然科学基金;
关键词
ADPKD; Autophagy; Calcium; mTOR; Saikosaponin-d; POLYCYSTIC KIDNEY-DISEASE; PHOSPHORYLATION; ACTIVATION; EXPRESSION; DEPENDENCE; GROWTH;
D O I
10.1007/s11010-018-3358-0
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Autosomal dominant polycystic kidney disease (ADPKD) is a common heritable human disease. Recently, the role of repressed autophagy in ADPKD has drawn increasing attention. Here, we investigate the mechanism underlying the effect of Saikosaponin-d (SSd), a sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump (SERCA) inhibitor. We show that SSd suppresses proliferation in ADPKD cells by up-regulating autophagy. We found that treatment with SSd results in the accumulation of intracellular calcium, which in turn activates the CaMKK beta-AMPK signalling cascade, inhibits mTOR signalling and induces autophagy. Conversely, we also found that treatment with an autophagy inhibitor (3-methyladenine), AMPK inhibitor (Compound C), CaMKK beta inhibitor (STO-609) and intracellular calcium chelator (BAPTA/AM) could reduce autophagy puncta formation mediated by SSd. Our results demonstrated that SSd induces autophagy through the CaMKK beta-AMPK-mTOR signalling pathway in ADPKD cells, indicating that SSd might be a potential therapy for ADPKD and that SERCA might be a new target for ADPKD treatment.
引用
收藏
页码:219 / 226
页数:8
相关论文
共 31 条
  • [1] Hypoxia-inducible factor-1α (HIF-1α) and autophagy in polycystic kidney disease (PKD)
    Belibi, Franck
    Zafar, Iram
    Ravichandran, Kameswaran
    Segvic, Anamarija Bauer
    Jani, Alkesh
    Ljubanovic, Danica Galesic
    Edelstein, Charles L.
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, 2011, 300 (05) : F1235 - F1243
  • [2] In vivo and in vitro antiinflammatory activity of saikosaponins
    Benito, PB
    Martínez, MJA
    Sen, AMS
    Gómez, AS
    Matellano, LF
    Contreras, SS
    Lanza, AMD
    [J]. LIFE SCIENCES, 1998, 63 (13) : 1147 - 1156
  • [3] Saikosaponin-d suppresses cell growth in renal cell carcinoma through EGFR/p38 signaling pathway
    Cai, C.
    Zhang, H.
    Ou, Y.
    Jiang, Y.
    Zhong, D.
    Qi, H.
    Dang, Q.
    [J]. NEOPLASMA, 2017, 64 (04) : 518 - 525
  • [4] Antiviral effects of saikosaponins on human coronavirus 229E in vitro
    Cheng, Pei-Win
    Ng, Lean-Teik
    Chiang, Lien-Chai
    Lin, Chun-Ching
    [J]. CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, 2006, 33 (07): : 612 - 616
  • [5] Mutations in SEC63 cause autosomal dominant polycystic liver disease
    Davila, S
    Furu, L
    Gharavi, AG
    Tian, X
    Onoe, T
    Qian, Q
    Li, AR
    Cai, YQ
    Kamath, PS
    King, BF
    Azurmendi, PJ
    Tahvanainen, P
    Kääriäinen, H
    Höckerstedt, K
    Devuyst, O
    Pirson, Y
    Martin, RS
    Lifton, RP
    Tahvanainen, E
    Torres, VE
    Somlo, S
    [J]. NATURE GENETICS, 2004, 36 (06) : 575 - 577
  • [6] Localized Cystic Disease of the Kidney Distinction From Cystic Neoplasms and Hereditary Polycystic Diseases
    Ding, Yi
    Chen, Longwen
    Deng, Fang-Ming
    Melamed, Jonathan
    Fan, Rong
    Bonsib, Stephen
    Zhou, Ming
    [J]. AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 2013, 37 (04) : 506 - 513
  • [7] Autophagy and neurodegeneration
    Frake, Rebecca A.
    Ricketts, Thomas
    Menzies, Fiona M.
    Rubinsztein, David C.
    [J]. JOURNAL OF CLINICAL INVESTIGATION, 2015, 125 (01) : 65 - 74
  • [8] Programmed Cell Death in Animal Development and Disease
    Fuchs, Yaron
    Steller, Hermann
    [J]. CELL, 2011, 147 (04) : 742 - 758
  • [9] AMPK phosphorylation of raptor mediates a metabolic checkpoint
    Gwinn, Dana M.
    Shackelford, David B.
    Egan, Daniel F.
    Mihaylova, Maria M.
    Mery, Annabelle
    Vasquez, Debbie S.
    Turk, Benjamin E.
    Shaw, Reuben J.
    [J]. MOLECULAR CELL, 2008, 30 (02) : 214 - 226
  • [10] Autosomal dominant polycystic kidney disease: clues to pathogenesis
    Harris, PC
    [J]. HUMAN MOLECULAR GENETICS, 1999, 8 (10) : 1861 - 1866