Small molecule inhibition of microRNA-21 expression reduces cell viability and microtumor formation

Ankenbruck, Nicholas; Kumbhare, Rohan; Naro, Yuta; Thomas, Melvin E.; Gardner, Laura; Emanuelson, Cole; Deiters, Alexander

doi:10.1016/j.bmc.2019.05.044

Cited by 15 publications

(13 citation statements)

References 43 publications

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“…The next day, four different treatments were performed in triplicate: (1) non-treated, (2) 100 µM doxorubicin, (3) UV irradiation for 2 min, or (4) 0.1% DMSO, all in regular DMEM. Cells were maintained at 37 °C and 5% CO 2 atmosphere for 72 h. An XTT cell viability assay 50 was performed by adding 40 µL of the activated XTT reagent (8 µL of 1.7 mg/mL menadione diluted into 1 mL of 1 mg/mL XTT reagent solution) to each well. Absorbance was measured at 450 nm and 630 nm (background) on a Tecan M1000 pro plate reader immediately following reagent addition.…”

Section: Methodsmentioning

confidence: 99%

Optical control of protein phosphatase function

Courtney

Deiters

2019

Nat Commun

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Protein phosphatases are involved in embryonic development, metabolic homeostasis, stress response, cell cycle transitions, and many other essential biological mechanisms. Unlike kinases, protein phosphatases remain understudied and less characterized. Traditional genetic and biochemical methods have contributed significantly to our understanding; however, these methodologies lack precise and acute spatiotemporal control. Here, we report the development of a light-activated protein phosphatase, the dual specificity phosphatase 6 (DUSP6 or MKP3). Through genetic code expansion, MKP3 is placed under optical control via two different approaches: (i) incorporation of a caged cysteine into the active site for controlling catalytic activity and (ii) incorporation of a caged lysine into the kinase interaction motif for controlling the protein-protein interaction between the phosphatase and its substrate. Both strategies are expected to be applicable to the engineering of a wide range of light-activated phosphatases. Applying the optogenetically controlled MKP3 in conjunction with live cell reporters, we discover that ERK nuclear translocation is regulated in a graded manner in response to increasing MKP3 activity.

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Section: Methodsmentioning

confidence: 99%

Optical control of protein phosphatase function

Courtney

Deiters

2019

Nat Commun

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“…For example, the miR-21 complementary binding site inserted downstream of the firefly luciferase gene at 3'UTR causes endogenous expression of the reporter gene to miR-21, resulting in decreased luminescence. On the contrary, functionally inhibited miR-21 can relieve the translation inhibition of luciferase and enhance fluorescence intensity [ 60 ]. In this high-throughput screening of more than 300,000 small molecules, a new class of acetamide miR-21 inhibitors has been found.…”

Section: Designing Strategies Of Small-molecule Compounds For Modulating Ncrnas In Cancermentioning

confidence: 99%

Designing strategies of small-molecule compounds for modulating non-coding RNAs in cancer therapy

Zhao

Zhu

et al. 2022

J Hematol Oncol

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Non-coding RNAs (ncRNAs) have been defined as a class of RNA molecules transcribed from the genome but not encoding proteins, such as microRNAs, long non-coding RNAs, Circular RNAs, and Piwi-interacting RNAs. Accumulating evidence has recently been revealing that ncRNAs become potential druggable targets for regulation of several small-molecule compounds, based on their complex spatial structures and biological functions in cancer therapy. Thus, in this review, we focus on summarizing some new emerging designing strategies, such as high-throughput screening approach, small-molecule microarray approach, structure-based designing approach, phenotypic screening approach, fragment-based designing approach, and pharmacological validation approach. Based on the above-mentioned approaches, a series of representative small-molecule compounds, including Bisphenol-A, Mitoxantrone and Enoxacin have been demonstrated to modulate or selectively target ncRNAs in different types of human cancers. Collectively, these inspiring findings would provide a clue on developing more novel avenues for pharmacological modulations of ncRNAs with small-molecule drugs for future cancer therapeutics.

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“…AGO is strongly downregulated in melanoma and re-expression could represent a therapeutic option [275,276]. The inhibitory effect of tumor-specific miRNAs on their target mRNAs could be inhibited by sequestering the miRNAs using, for example, lncRNAs as competing endogenous RNAs (ceRNAs) [277][278][279], by small-molecule inhibitors [280] or modified oligoribonucleotides (e.g., LNAs) [281]. Those can be specifically delivered into tumor cells using a nanoparticle based system [282].…”

Section: Genetic Alterations Transcriptional Regulation and Mirna-edmentioning

confidence: 99%

“…Another possibility to clinically target miRNAs is the use of small-molecule inhibitors (Figure 9). A reporter gene-based screen with over 300,000 different compounds lead to the identification of for example, a specific and efficient inhibitor of miR-21 transcription inducing apoptosis of the cervical carcinoma cell line HeLa and preventing assembly of microtumors in low doses in vitro [280].…”

Section: Therapeutic Targeting Of Mirnas and Mirna-pathwaysmentioning

confidence: 99%

Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

Linck-Paulus

Hellerbrand

Bosserhoff

et al. 2020

Cells

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In this review, we summarize the current knowledge on miRNAs as therapeutic targets in two cancer types that were frequently described to be driven by miRNAs—melanoma and hepatocellular carcinoma (HCC). By focusing on common microRNAs and associated pathways in these—at first sight—dissimilar cancer types, we aim at revealing similar molecular mechanisms that are evolved in microRNA-biology to drive cancer progression. Thereby, we also want to outlay potential novel therapeutic strategies. After providing a brief introduction to general miRNA biology and basic information about HCC and melanoma, this review depicts prominent examples of potent oncomiRs and tumor-suppressor miRNAs, which have been proven to drive diverse cancer types including melanoma and HCC. To develop and apply miRNA-based therapeutics for cancer treatment in the future, it is essential to understand how miRNA dysregulation evolves during malignant transformation. Therefore, we highlight important aspects such as genetic alterations, miRNA editing and transcriptional regulation based on concrete examples. Furthermore, we expand our illustration by focusing on miRNA-associated proteins as well as other regulators of miRNAs which could also provide therapeutic targets. Finally, design and delivery strategies of miRNA-associated therapeutic agents as well as potential drawbacks are discussed to address the question of how miRNAs might contribute to cancer therapy in the future.

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Small molecule inhibition of microRNA-21 expression reduces cell viability and microtumor formation

Cited by 15 publications

References 43 publications

Optical control of protein phosphatase function

Optical control of protein phosphatase function

Designing strategies of small-molecule compounds for modulating non-coding RNAs in cancer therapy

Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

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