Fluvastatin Interferes with Hepatitis C Virus Replication via Microtubule Bundling and a Doublecortin-like Kinase-Mediated Mechanism

被引:29
作者
Ali, Naushad [1 ,3 ,4 ]
Allam, Heba [1 ,6 ]
Bader, Ted [1 ,4 ]
May, Randal [1 ,4 ]
Basalingappa, Kanthesh M. [1 ]
Berry, William L. [2 ]
Chandrakesan, Parthasarathy [1 ]
Qu, Dongfeng [1 ]
Weygant, Nathaniel [1 ]
Bronze, Michael S. [1 ]
Umar, Shahid [5 ]
Janknecht, Ralf [2 ,3 ]
Sureban, Sripathi M. [1 ,3 ,4 ]
Huycke, Mark [1 ,3 ,4 ]
Houchen, Courtney W. [1 ,3 ,4 ]
机构
[1] Univ Oklahoma, Dept Med, Sect Digest Dis & Nutr, Oklahoma City, OK 73190 USA
[2] Univ Oklahoma, Dept Cell Biol, Oklahoma City, OK USA
[3] Univ Oklahoma, Univ Oklahoma Hlth Sci Ctr, Peggy & Charles Stephenson Canc Ctr, Oklahoma City, OK USA
[4] Univ Oklahoma, Dept Vet Affairs Med Ctr, Oklahoma City, OK USA
[5] Univ Kansas, Med Ctr, Dept Mol & Integrat Physiol & Med, Kansas City, KS 66103 USA
[6] Menoufia Univ, Dept Microbiol & Immunol, Menoufia, Egypt
来源
PLOS ONE | 2013年 / 8卷 / 11期
关键词
RNA REPLICATION; HCV REPLICATION; GENOTYPE; 1B; STATINS; TUMOR; RIBAVIRIN; THERAPY; LIVER; COMBINATION; INHIBITION;
D O I
10.1371/journal.pone.0080304
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Hepatitis C virus (HCV)-induced alterations in lipid metabolism and cellular protein expression contribute to viral pathogenesis. The mechanism of pleiotropic actions of cholesterol-lowering drugs, statins, against HCV and multiple cancers are not well understood. We investigated effects of fluvastatin (FLV) on microtubule-associated and cancer stem cell marker (CSC), doublecortin-like kinase 1 (DCLK1) during HCV-induced hepatocarcinogenesis. HCV replication models, cancer cell lines and normal human hepatocytes were used to investigate the antiviral and antitumor effects of statins. FLV treatment resulted in induction of microtubule bundling, cell-cycle arrest and alterations in cellular DCLK1 distribution in HCV-expressing hepatoma cells. These events adversely affected the survival of liver-derived tumor cells without affecting normal human hepatocytes. FLV downregulated HCV replication in cell culture where the ATP pool and cell viability were not compromised. Pravastatin did not exhibit these effects on HCV replication, microtubules and cancer cells. The levels of miR-122 that regulates liver homeostasis and provides HCV genomic stability remained at steady state whereas DCLK1 mRNA levels were considerably reduced during FLV treatment. We further demonstrated that HCV replication was increased with DCLK1 overexpression. In conclusion, unique effects of FLV on microtubules and their binding partner DCLK1 are likely to contribute to its anti-HCV and antitumor activities in addition to its known inhibitory effects on 3-hydroxy-3-methylglutary-CoA reductase (HMGCR).
引用
收藏
页数:10
相关论文
共 45 条
  • [1] Cell-free replication of the hepatitis C virus subgenomic replicon
    Ali, N
    Tardif, KD
    Siddiqui, A
    [J]. JOURNAL OF VIROLOGY, 2002, 76 (23) : 12001 - 12007
  • [2] Hepatitis C Virus-Induced Cancer Stem Cell-Like Signatures in Cell Culture and Murine Tumor Xenografts
    Ali, Naushad
    Allam, Heba
    May, Randal
    Sureban, Sripathi M.
    Bronze, Michael S.
    Bader, Ted
    Umar, Shahid
    Anant, Srikant
    Houchen, Courtney W.
    [J]. JOURNAL OF VIROLOGY, 2011, 85 (23) : 12292 - 12303
  • [3] Combination of fluvastatin with pegylated interferon/ribavirin therapy reduces viral relapse in chronic hepatitis C infected with HCV genotype 1b
    Atsukawa, Masanori
    Tsubota, Akihito
    Kondo, Chisa
    Itokawa, Norio
    Narahara, Yoshiyuki
    Nakatsuka, Katsuhisa
    Hashimoto, Satomi
    Fukuda, Takeshi
    Matsushita, Yoko
    Kidokoro, Hideko
    Kobayashi, Tamaki
    Kanazawa, Hidenori
    Sakamoto, Choitsu
    [J]. JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 2013, 28 (01) : 51 - 56
  • [4] Bader T HL, 2013, J VIRAL HEP IN PRESS
  • [5] Fluvastatin inhibits hepatitis C replication in humans
    Bader, Ted
    Fazili, Javid
    Madhoun, Mohammed
    Aston, Christopher
    Hughes, Diane
    Rizvi, Syed
    Seres, Ken
    Hasan, Muhammad
    [J]. AMERICAN JOURNAL OF GASTROENTEROLOGY, 2008, 103 (06) : 1383 - 1389
  • [6] Assembly of infectious hepatitis C virus particles
    Bartenschlager, Ralf
    Penin, Francois
    Lohmann, Volker
    Andre, Patrice
    [J]. TRENDS IN MICROBIOLOGY, 2011, 19 (02) : 95 - 103
  • [7] Microtubule-interacting drugs for cancer treatment
    Checchi, PM
    Nettles, JH
    Zhou, J
    Snyder, JP
    Joshi, HC
    [J]. TRENDS IN PHARMACOLOGICAL SCIENCES, 2003, 24 (07) : 361 - 365
  • [8] Targeting tumor cell metabolism with statins
    Clendening, J. W.
    Penn, L. Z.
    [J]. ONCOGENE, 2012, 31 (48) : 4967 - 4978
  • [9] Explaining statin inhibition effectiveness of HMG-CoA reductase by quantum biochemistry computations
    da Costa, Roner F.
    Freire, Valder N.
    Bezerra, Eveline M.
    Cavada, Benildo S.
    Caetano, Ewerton W. S.
    de Lima Filho, Jose L.
    Albuquerque, Eudenilson L.
    [J]. PHYSICAL CHEMISTRY CHEMICAL PHYSICS, 2012, 14 (04) : 1389 - 1398
  • [10] Statins Potentiate the In Vitro Anti-Hepatitis C Virus Activity of Selective Hepatitis C Virus Inhibitors and Delay or Prevent Resistance Development
    Delang, Leen
    Paeshuyse, Jan
    Vliegen, Inge
    Leyssen, Pieter
    Obeid, Susan
    Durantel, David
    Zoulim, Fabien
    de Beeck, Anne Op
    Neyts, Johan
    [J]. HEPATOLOGY, 2009, 50 (01) : 6 - 16