Imiquimod-induced AMPK activation causes translation attenuation and apoptosis but not autophagy

Wang, Sin Ting; Huang, Shi; Kao, Jun Kai; Liang, Shu‐Mei; Chen, Yi Ju; Chen, Yu Yu; Wu, Chun Ying; Shieh, Jeng-Jer

doi:10.1016/j.jdermsci.2015.02.008

Cited by 20 publications

(18 citation statements)

References 39 publications

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“…El-Khattouti et al hypothesized that ER stress pathways are mediated through TLR7 activation [21], however we could not detect any expression of TLR7 in our cell lines prior to or after imiquimod treatment. As previous studies have also reported TLR7 independent activation of apoptosis in imiquimod treated tumour cell lines [13, 15, 18, 19, 37], we suggest imiquimod induces ER stress via alternative mechanisms.…”

Section: Discussionsupporting

confidence: 72%

“…In addition, cell culture studies have demonstrated direct activation of tumour cell apoptosis and autophagy in response to imiquimod treatment [13–17]. Imiquimod exerts these effects in a tumour specific manner, independently of both TLR7 signaling and immune cell function [13, 15, 18, 19]. Pro- and anti-apoptotic proteins, such as Noxa, BCL2 and MCL1, are involved in the regulation of these apoptotic pathways, and more recently both oxidative and endoplasmic reticulum (ER) stress pathways have also been implicated [14, 18–21].…”

Section: Introductionmentioning

confidence: 99%

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The Immunomodulatory Small Molecule Imiquimod Induces Apoptosis in Devil Facial Tumour Cell Lines

et al. 2016

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The survival of the Tasmanian devil (Sarcophilus harrisii) is threatened by devil facial tumour disease (DFTD). This transmissible cancer is usually fatal, and no successful treatments have been developed. In human studies, the small immunomodulatory molecule imiquimod is a successful immunotherapy, activating anti-tumour immunity via stimulation of toll-like receptor-7 (TLR7) signaling pathways. In addition, imiquimod is a potent inducer of apoptosis in human tumour cell lines via TLR7 independent mechanisms. Here we investigate the potential of imiquimod as a DFTD therapy through analysis of treated DFTD cell lines and Tasmanian devil fibroblasts. WST-8 proliferation assays and annexin V apoptosis assays were performed to monitor apoptosis, and changes to the expression of pro- and anti-apoptotic genes were analysed using qRT-PCR. Our results show that DFTD cell lines, but not Tasmanian devil fibroblasts, are sensitive to imiquimod-induced apoptosis in a time and concentration dependent manner. Induction of apoptosis was accompanied by down-regulation of the anti-apoptotic BCL2 and BCLXL genes, and up-regulation of the pro-apoptotic BIM gene. Continuous imiquimod treatment was required for these effects to occur. These results demonstrate that imiquimod can deregulate DFTD cell growth and survival in direct and targeted manner. In vivo, this may increase DFTD vulnerability to imiquimod-induced TLR7-mediated immune responses. Our findings have improved the current knowledge of imiquimod action in tumour cells for application to both DFTD and human cancer therapy.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

The Immunomodulatory Small Molecule Imiquimod Induces Apoptosis in Devil Facial Tumour Cell Lines

et al. 2016

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“…It has been demonstrated that roscovitine has significant anti-tumor effects (26–28) and can downregulate Mcl-1 expression (7). Other studies have confirmed that upregulation of AMPK activation inhibits the expression of Mcl-1 (8–10). In the present study, it was observed that roscovitine protected mice and their testes from inflammatory injury.…”

Section: Discussionmentioning

confidence: 76%

“…Other studies have shown that upregulation of adenosine monophosphate-activated protein kinase (AMPK) activation also inhibited the expression of Mcl-1 (8–10). AMPK is an important regulator of energy homeostasis in cells.…”

Section: Introductionmentioning

confidence: 99%

Roscovitine protects murine Leydig cells from lipopolysaccharide-induced inflammation

Xie

Dong

et al. 2017

Experimental and Therapeutic Medicine

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Roscovitine is a cyclin-dependent kinase inhibitor, which has been previously investigated for its anticancer effects. It has also been confirmed that roscovitine can downregulate the expression of myeloid cell leukemia-1 protein to inhibit inflammation. In the present study, roscovitine was used to treat inflammation in lipopolysaccharide (LPS)-induced model mice. At the cellular level, Leydig cells isolated from mouse testis were assessed for inflammatory factors. It was revealed that roscovitine successfully reduced inflammation-associated injury induced by LPS pretreatment. At the molecular level, roscovitine was found to exert this effect through promotion of adenosine monophosphate-activated protein kinase phosphorylation. To the best of our knowledge, the present study was the first to suggest that roscovitine has a protective role in Leydig cells through its anti-inflammatory action.

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“…The method used for RNA extraction and reverse transcription-PCR (RT-PCR) was as described previously [24]. Briefly, total RNA was extracted by TRIZO reagent (Invitrogen) and utilized RNA extracts to synthesize first strand cDNA according to kit manual, Sprint PowerScript PrePrimed Single Shots Kit (Clontech, Mountain View, CA, USA).…”

Section: Detection Of Xbp1 Mrna Splicingmentioning

confidence: 99%

Imiquimod-induced autophagy is regulated by ER stress-mediated PKR activation in cancer cells

Chang

Huang

Wang

et al. 2017

Journal of Dermatological Science

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Imiquimod-induced AMPK activation causes translation attenuation and apoptosis but not autophagy

Cited by 20 publications

References 39 publications

The Immunomodulatory Small Molecule Imiquimod Induces Apoptosis in Devil Facial Tumour Cell Lines

The Immunomodulatory Small Molecule Imiquimod Induces Apoptosis in Devil Facial Tumour Cell Lines

Roscovitine protects murine Leydig cells from lipopolysaccharide-induced inflammation

Imiquimod-induced autophagy is regulated by ER stress-mediated PKR activation in cancer cells

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