The Antiparasitic Clioquinol Induces Apoptosis in Leukemia and Myeloma Cells by Inhibiting Histone Deacetylase Activity

Cao, Biyin; Li, Jie; Zhu, Jingyu; Shen, Meifen; Han, Kai; Zhang, Zubin; Yu, Yang; Wang, Yali; Wu, Depei; Chen, Suning; Sun, Aining; Tang, Xiaowen; Zhao, Yun; Qiao, Chunhua; Hou, Tingjun; Mao, Xinliang

doi:10.1074/jbc.m113.472563

Cited by 43 publications

(38 citation statements)

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“…For example, the HDAC inhibitor SAHA was found to induce autophagic cell death24. Our recent study demonstrated that clioquinol can also inhibit HDACs10, but whether clioquinol-induced autophagy is due to its action as an inhibitor of proteasomes or as an inhibitor of HDAC is not clear yet, the present study showed that clioquinol induces both apoptosis and autophagy. Moreover, its action on apoptosis can be partly abrogated by 3-MA, a major inhibitor of autophagy.…”

Section: Discussionsupporting

confidence: 44%

Clioquinol induces pro-death autophagy in leukemia and myeloma cells by disrupting the mTOR signaling pathway

Cao

Zhou

et al. 2014

Sci Rep

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Clioquinol is an anti-microbial drug, and it was recently found to induce cancer cell death. In the present study, clioquinol was found to trigger autophagy by inducing LC3 lipidation and autophagosome formation which was abolished by an autophagy inhibitor 3-methyladenine. Further study showed clioquinol displayed no effects on PI3KC3 or Beclin 1 expression but downregulated the expression and the enzymatic activity of mammalian target of Rapamycin (mTOR), a critical modulator of autophagy. Moreover, clioquinol inhibited the catalytic activity of the mTOR complex 1, thus suppressing phosphorylation of P70S6K and 4E-BP1, two major proteins associated with autophagy in the mTORC1 signaling pathway. Clioquinol induced leukemia and myeloma cell apoptosis, however, addition of autophagy inhibitor 3-methyladenine attenuated this kind of cell death. Therefore, this study demonstrated that clioquinol induces autophagy in associated with apoptosis in leukemia and myeloma cells by disrupting mTOR signaling pathway.

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Section: Discussionsupporting

confidence: 44%

Clioquinol induces pro-death autophagy in leukemia and myeloma cells by disrupting the mTOR signaling pathway

Cao

Zhou

et al. 2014

Sci Rep

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“…In addition to the effects on histone transcription factors, a lot of HDAC inhibitors are known that they can affect non-histone transcription factors including p53 and tubulin [35,36]. In thyroid cancers, HDAC inhibitors sodium butyrate and trichostatin A have been reported to inhibit the growth of anaplastic thyroid cancer cells due to the promotion of apoptosis and the induction of cell cycle arrest, both of which are independent of p53 status [37].…”

Section: Discussionmentioning

confidence: 99%

The novel histone deacetylase inhibitor thailandepsin A inhibits anaplastic thyroid cancer growth

Weinlander

Somnay

Harrison

et al. 2014

Journal of Surgical Research

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Background Anaplastic thyroid cancer (ATC) remains refractory to available surgical and medical interventions. Histone deacetylase (HDAC) inhibitors are an emerging targeted therapy with anti-proliferative activity in a variety of thyroid cancer cell lines. Thailandepsin A (TDP-A) is a novel class I HDAC inhibitor whose efficacy remains largely unknown in ATC. Therefore, we aimed to characterize the effect of TDP-A on ATC. Methods Human-derived ATC cells were treated with TDP-A. IC50 was determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) rapid colorimetric assay and cell proliferation was measured by viable cell count. Molecular mechanisms of cell growth inhibition were investigated by Western blot analysis of canonical apoptosis markers, intrinsic and extrinsic apoptosis regulators, and cell cycle regulatory proteins. Cell cycle staging was determined with propidium iodide flow cytometry. Results TDP-A dose- and time-dependently reduced cell proliferation. Increased cleavage of the apoptosis markers Caspase-9, Caspase-3, and poly ADP ribose polymerase (PARP) were observed with TDP-A treatment. Levels of the intrinsic apoptosis pathway proteins BAD, Bcl-XL, and BAX remained unchanged. Importantly, the extrinsic apoptosis activator cleaved Caspase-8 increased dose-dependently and the anti-apoptotic proteins Survivin and Bcl-2 decreased. Among the cell cycle regulatory proteins, levels of CDK inhibitors p21/WAF1 and p27/KIP increased. Flow cytometry showed that ATC cells were arrested in G2/M phase with diminished S phase following TDP-A treatment. Conclusion TDP-A induces a notable dose- and time-dependent anti-proliferative effect on ATC, which is mainly attributed to extrinsic apoptosis with concomitant cell cycle arrest. TDP-A therefore warrants further preclinical and clinical investigations.

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“…Current studies have demonstrated that proteasomal inhibitors can modulate gene transcription in addition to modulating protein stability. Proteasomal inhibitors such as bortezomib and clioquinol have been demonstrated to regulate gene transcription by inhibiting histone deacetylases, thus regulating gene expression in an epigenetic manner (22,23).…”

Section: Discussionmentioning

confidence: 99%

The Ring Finger Protein RNF6 Induces Leukemia Cell Proliferation as a Direct Target of Pre-B-cell Leukemia Homeobox 1

Han

Tang

et al. 2016

Journal of Biological Chemistry

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RNF6 is a little-studied ring finger protein. In the present study, we found that RNF6 was overexpressed in various leukemia cells and that it accelerated leukemia cell proliferation, whereas knockdown of RNF6 delayed tumor growth in xenografts. To find out the mechanism of RNF6 overexpression in leukemia, we designed a series of truncated constructs of RNF6 regulatory regions in the luciferase reporter system. The results revealed that the region between ؊144 and ؊99 upstream of the RNF6 transcription start site was critical and that this region contained a PBX1 recognition element (PRE). PBX1 modulated RNF6 expression by binding to the specific PRE. When PRE was mutated, RNF6 transcription was completely abolished. Further studies showed that PBX1 collaborated with PREP1 but not MEIS1 to modulate RNF6 expression. Moreover, RNF6 expression could be suppressed by doxorubicin, a major anti-leukemia agent, via down-regulating PBX1. This study thus suggests that RNF6 overexpression in leukemia is under the direction of PBX1 and that the PBX1/RNF6 axis can be developed as a novel therapeutic target of leukemia.The ring finger protein 6 (RNF6) belongs to the largest RING ubiquitin ligase family, and it is mapped to chromosome band 13q12.2, a harbor of several critical tumor suppressor genes (1). RNF6 is believed to be a tumor suppressor because of its chromosomal location and somatic mutations in esophageal squamous cell carcinomas (2), but confirmative evidence is not available. In contrast, recent studies suggest that RNF6 is probably an oncogene. RNF6 is found at a high level in prostate cancers. As a ubiquitin ligase, RNF6 interacts with androgen receptor (AR) 3 and mediates atypical polyubiquitination chains at Lys-6 and Lys-27, thus promoting the transcriptional activity of AR by facilitating its binding to the coactivators (3). By modulating AR function, RNF6 promotes prostate cancer cell growth. In contrast, mutations and specific knockdown of RNF6 alter AR transcriptional activity and delay prostate cancer growth in xenograft models (3). RNF6 is also elevated in cisplatin-resistant human lung adenocarcinoma cells (4). Therefore, RNF6 probably plays a critical role in tumorigenesis and chemoresistance. However, the studies on RNF6 are very limited, and the biological functions and modulation of RNF6 are largely unknown.In the present study, we evaluated the RNF6 function in leukemia cells and found that RNF6 is overexpressed in leukemia cells and contributes to leukemia cell proliferation. Furthermore, RNF6 overexpression in leukemia is found to be modulated by the transcription factor PBX1, the pre-B-cell leukemia homeobox 1.

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The Antiparasitic Clioquinol Induces Apoptosis in Leukemia and Myeloma Cells by Inhibiting Histone Deacetylase Activity

Cited by 43 publications

References 50 publications

Clioquinol induces pro-death autophagy in leukemia and myeloma cells by disrupting the mTOR signaling pathway

Clioquinol induces pro-death autophagy in leukemia and myeloma cells by disrupting the mTOR signaling pathway

The novel histone deacetylase inhibitor thailandepsin A inhibits anaplastic thyroid cancer growth

The Ring Finger Protein RNF6 Induces Leukemia Cell Proliferation as a Direct Target of Pre-B-cell Leukemia Homeobox 1

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