<i>FBW7</i>-Dependent Mcl-1 Degradation Mediates the Anticancer Effect of Hsp90 Inhibitors

Tong, Jingshan; Tan, Shuai; Nikolovska‐Coleska, Zaneta; Yu, Jian; Zou, Fangdong; Zhang, Lin

doi:10.1158/1535-7163.mct-17-0032

Cited by 60 publications

(58 citation statements)

References 43 publications

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“…OA is prevalent on the articular surfaces of the hands, elbows, hips, and knees [27]. Joint cartilage, ligaments, subchondral bone, capsule, and adjacent muscles are vulnerable to OA [28,29]. Currently, it is widely accepted that OA is The miRNA family consists of single chain, non-coding small RNA molecules that are usually twenty-two to twenty-three nucleotides in length [33,34].…”

Section: Discussionmentioning

confidence: 99%

MiR-34a Enhances Chondrocyte Apoptosis, Senescence and Facilitates Development of Osteoarthritis by Targeting DLL1 and Regulating PI3K/AKT Pathway

Zhang

Hsu

Zhong

et al. 2018

Cell Physiol Biochem

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Background/Aims: Osteoarthritis (OA) is the prevalent degenerative disease caused by various factors. MicroRNAs are important regulators in the inflammation and immune response. The aim of this study was to investigate the effect of microRNA-34a (MiR-34a) on the death of chondrocytes, senescence, as well as its role in OA progression. Methods: A series of experiments involving CCK-8, flow cytometry, β-galactosidase staining and wound healing assays were conducted to determine the cellular capabilities of proliferation, cell apoptosis, senescence and the ability of cells to recover from injury, respectively. Binding sites between miR-34a and delta-like protein 1 (DLL1) were identified using a luciferase reporter system, whereas mRNA and protein expression of target genes was determined by RT-PCR and immunoblot, respectively. OA model was generated via surgery. Results: We found that miR-34a expression was increased in the cartilage of OA patients. In rat chondrocytes and chondrosarcoma cells, miR-34a transfections noticeably inhibited the expression of DLL1, triggered cell death and senescence, suppressed proliferation, and prevented scratch assay wound closure. However, transfection of a miR-34a inhibitor displayed adverse effects. Additionally, secretion and expression of factors associated with cartilage degeneration were altered via miR-34a. Moreover, miR-34a directly inhibits DLL1 mRNA. Furthermore, concentrations of DLL1, total PI3K, and p-AKT declined in chondrocytes that overexpress miR-34a. DLL1 overexpression elevated PI3K and p-AKT levels, and eliminated cell death triggered by a miR-34a mimic. In vivo, miR-34a remarkably inhibited miR-34a up-regulation, while enhanced the level of DLL1 expression. In the knee joints of surgery-induced OA rats, articular chondrocyte death and loss of cartilage were attenuated via miR-34a antagomir injection. Conclusions: These findings indicate that miR-34a contributes to chondrocyte death, causing OA progression through DLL1 and modulation of the PI3K/AKT pathway.

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Section: Discussionmentioning

confidence: 99%

MiR-34a Enhances Chondrocyte Apoptosis, Senescence and Facilitates Development of Osteoarthritis by Targeting DLL1 and Regulating PI3K/AKT Pathway

Zhang

Hsu

Zhong

et al. 2018

Cell Physiol Biochem

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“…Western blot assay was performed as previously described. 31,32 Total cell protein was isolated using NP40 lysates in the presence of inhibitors of proteases and phosphatases. The proteins were separated by SDS-PAGE and transferred to PVDF membranes.…”

Section: Western Blot Assaymentioning

confidence: 99%

Bromodomain and extraterminal domain inhibitor enhances the antitumor effect of imatinib in gastrointestinal stromal tumours

Sun²,

et al. 2020

J Cellular Molecular Medi

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In gastrointestinal stromal tumours (GISTs), the function of bromodomain‐containing 4 (BRD4) remains underexplored. BRD4 mRNA abundance was quantified in GISTs. In the current study, we investigated the role of BRD4 in GISTs. Our results show a significant enhancement in BRD4 mRNA and a shift from very low‐risk/low‐risk to high‐risk levels as per NCCN specifications. Overexpression of BRD4 correlated with unfavourable genotype, nongastric location, enhanced risk and decreased disease‐free survival, which were predicted independently. Knockout of BRD4 in vitro suppressed KIT expression, which led to inactivation of the KIT/PI3K/AKT/mTOR pathway, impeded migration and cell growth and made the resistant GIST cells sensitive to imatinib. The expression of KIT was repressed by a BRD4 inhibitor JQ1, which also induced myristoylated‐AKT‐suppressible caspases 3 and 9 activities, induced LC3‐II, exhibited dose‐dependent therapeutic synergy with imatinib and attenuated the activation of the PI3K/AKT/mTOR pathway. In comparison with their single therapy, the combination of JQ1/imatinib more efficiently suppressed the growth of xenografts and exhibited a reduction in KIT phosphorylation, a decrease in Ki‐67 and in the levels of phosphorylated PI3K/AKT/mTOR and enhanced TUNEL staining. Thus, we characterized the biological, prognostic and therapeutic implications of overexpressed BRD4 in GIST and observed that JQ1 suppresses KIT transactivation and nullifies the activation of PI3K/AKT/mTOR, providing a potential strategy for treating imatinib‐resistant GIST through dual blockade of KIT and BRD4.

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“…Colon cancer cells carrying mutant FBW7 are reported to be resistant to inhibition of HSP90, in which mutant FBW7 fails to degrade Mcl‐1 leading to Mcl‐1's stabilization . HCT116 and SW480 cells used in this manuscript harbor wild‐type FBW7 .…”

Section: Discussionmentioning

confidence: 99%

BAG3‐dependent expression of Mcl‐1 confers resistance of mutant KRAS colon cancer cells to the HSP90 inhibitor AUY922

Wang

Guo

Croft

et al. 2017

Molecular Carcinogenesis

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Past studies have shown that mutant KRAS colon cancer cells are susceptible to apoptosis induced by the HSP90 inhibitor AUY922. Nevertheless, intrinsic and acquired resistance remains an obstacle for the potential application of the inhibitor in the treatment of the disease. Here we report that Mcl-1 is important for survival of colon cancer cells in the presence of AUY922. Mcl-1 was upregulated in mutant KRAS colon cancer cells selected for resistance to AUY922-induced apoptosis. This was due to its increased stability mediated by Bcl-2-associated athanogene domain 3 (BAG3), which was also increased in resistant colon cancer cells by heat shock factor 1 (HSF1) as a result of chronic endoplasmic reticulum (ER) stress. Functional investigations demonstrated that inhibition of Mcl-1, BAG3, or HSF1 triggered apoptosis in resistant colon cancer cells, and rendered AUY922-naïve colon cancer cells more sensitive to the inhibitor. Together, these results identify that the HSF1-BAG3-Mcl-1 signal axis is critical for protection of mutant KRAS colon cancer cells from AUY922-induced apoptosis, with potential implications for targeting HSF1/BAG3/Mcl-1 to improve the efficacy of AUY922 in the treatment of colon cancer.

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FBW7-Dependent Mcl-1 Degradation Mediates the Anticancer Effect of Hsp90 Inhibitors

Cited by 60 publications

References 43 publications

MiR-34a Enhances Chondrocyte Apoptosis, Senescence and Facilitates Development of Osteoarthritis by Targeting DLL1 and Regulating PI3K/AKT Pathway

MiR-34a Enhances Chondrocyte Apoptosis, Senescence and Facilitates Development of Osteoarthritis by Targeting DLL1 and Regulating PI3K/AKT Pathway

Bromodomain and extraterminal domain inhibitor enhances the antitumor effect of imatinib in gastrointestinal stromal tumours

BAG3‐dependent expression of Mcl‐1 confers resistance of mutant KRAS colon cancer cells to the HSP90 inhibitor AUY922

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