Targeting cyclin D3/<scp>CDK</scp>6 activity for treatment of Parkinson's disease

Alquézar, Carolina; Barrio, Estíbaliz; Esteras, Noemí; Encarnación, Ana de la; Molina, José Antonio; Martín-Requero, Ángeles

doi:10.1111/jnc.13070

Cited by 18 publications

(7 citation statements)

References 53 publications

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“…Within these clusters, CDK6 and HES5 were consistently found. CDK6 (targeted by miR-15b-5p) has been shown to be hyperactive in PD patients and was shown to be a promising therapeutic target by Alquézar et al, [89]. CDK6 is also an interacting partner of TDP43 [90], a gene known to be dysregulated in ALS [40] and in frontotemporal lobular dementia [91].…”

Section: Resultsmentioning

confidence: 99%

Panoramic Visualization of Circulating MicroRNAs Across Neurodegenerative Diseases in Humans

Brennan¹,

Keon²,

Liu³

et al. 2019

Mol Neurobiol

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Neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and dementia pose one of the greatest health challenges this century. Although these NDs have been looked at as single entities, the underlying molecular mechanisms have never been collectively visualized to date. With the advent of high-throughput genomic and proteomic technologies, we now have the opportunity to visualize these diseases in a whole new perspective, which will provide a clear understanding of the primary and secondary events vital in achieving the final resolution of these diseases guiding us to new treatment strategies to possibly treat these diseases together. We created a knowledge base of all microRNAs known to be differentially expressed in various body fluids of ND patients. We then used several bioinformatic methods to understand the functional intersections and differences between AD, PD, ALS, and MS. These results provide a unique panoramic view of possible functional intersections between AD, PD, MS, and ALS at the level of microRNA and their cognate genes and pathways, along with the entities that unify and separate them. While the microRNA signatures were apparent for each ND, the unique observation in our study was that hsa-miR-30b-5p overlapped between all four NDS, and has significant functional roles described across NDs. Furthermore, our results also show the evidence of functional convergence of miRNAs which was associated with the regulation of their cognate genes represented in pathways that included fatty acid synthesis and metabolism, ECM receptor interactions, prion diseases, and several signaling pathways critical to neuron differentiation and survival, underpinning their relevance in NDs. Envisioning this group of NDs together has allowed us to propose new ways of utilizing circulating miRNAs as biomarkers and in visualizing diverse NDs more holistically . The critical molecular insights gained through the discovery of ND-associated miRNAs, overlapping miRNAs, and the functional convergence of microRNAs on vital pathways strongly implicated in neurodegenerative processes can prove immensely valuable in the identifying new generation of biomarkers, along with the development of miRNAs into therapeutics.Electronic supplementary materialThe online version of this article (10.1007/s12035-019-1615-1) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Panoramic Visualization of Circulating MicroRNAs Across Neurodegenerative Diseases in Humans

Brennan¹,

Keon²,

Liu³

et al. 2019

Mol Neurobiol

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“…Tumor cells have stronger proliferation ability than normal cells, so most tumor cells have more cells in the S phase, and Cyclin D protein expression is higher. If Cyclin D-CDK4/CDK6 complex expression is inhibited, it can inhibit the cell cycle process and promote cell aging, which is expected to become a new therapeutic target (Alquézar et al, 2015;Fan et al, 2017;Wang et al, 2017). In this experiment, β-elemene can reduce cell proliferation by inhibiting the cell cycle, and Cyclin D3 may become one of the targets for β-elemene to reverse the resistance to 5-Fu in p53-deficient colorectal cancer.…”

Section: Discussionmentioning

confidence: 97%

β-Elemene Reverses the Resistance of p53-Deficient Colorectal Cancer Cells to 5-Fluorouracil by Inducing Pro-death Autophagy and Cyclin D3-Dependent Cycle Arrest

Zhang

Pan

et al. 2020

Front. Bioeng. Biotechnol.

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Objective: Colorectal cancer is a malignant tumor of the digestive system with high morbidity and mortality. 5-fluorouracil remains a widely used chemotherapeutic drug in the treatment of advanced colorectal cancer, but chemotherapy drugs are prone to develop drug resistance, p53 deletion or mutation is an important reason for the resistance of colorectal cancer cells to 5-fluorouracil. β-elemene has been proved to have the potential of reverse chemotherapy drug resistance, but the mechanism is unknown. This study aimed to investigate the effect of β-elemene to 5-fluorouracil in drug-resistant p53-deficient colorectal cancer cells HCT116p53 −/− , and determine the possible molecular mechanism of β-elemene to reverse 5-fluorouracil resistance. Methods: The effect of β-elemene on HCT116p53 −/− cell activity was detected by Cell counting Kit-8. Cell proliferation was detected by monoclonal plate. The apoptosis was detected by flow cytometry and western blot. The autophagy was detected by western blot, immunofluorescence and transmission electron microscope. Determine the role of Cyclin-related protein Cyclin D3 in β-elemene reversing the resistance of HCT116p53 −/− to 5-fluorouracil was detected by overexpression of Cyclin D3. The effect of β-elemene on the tumorigenic ability of p53-deficient colorectal cancer cells was detected establishing HCT116p53 −/− all line xenograft model. Results: For p53 wildtype colorectal cancer cells, β-elemene could augment the sensitivity of 5-fluorouracil, for p53-deficient colorectal cancer cells, β-elemene significantly inhibited cell proliferation in a concentration-dependent manner, and

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“…CDK6 has been implicated in the proliferation, differentiation, and survival of neurons (Beukelaers et al, 2011; Mi et al, 2013; Caron et al, 2018; Hasenpusch-Theil et al, 2018). For example, preventing CDK6 over-activation can reduce 6-hydroxy-dopamine-induced neuronal death (Alquezar et al, 2015). According to previous studies, CDK6 is localized to the cytoplasm (Kohrt et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Silencing of lncRNA PKIA-AS1 Attenuates Spinal Nerve Ligation-Induced Neuropathic Pain Through Epigenetic Downregulation of CDK6 Expression

Rong

et al. 2019

Front. Cell. Neurosci.

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Neuropathic pain (NP) is among the most intractable comorbidities of spinal cord injury. Dysregulation of non-coding RNAs has also been implicated in the development of neuropathic pain. Here, we identified a novel lncRNA, PKIA-AS1, by using lncRNA array analysis in spinal cord tissue of spinal nerve ligation (SNL) model rats, and investigated the role of PKIA-AS1 in SNL-mediated neuropathic pain. We observed that PKIA-AS1 was significantly upregulated in SNL model rats and that PKIA-AS1 knockdown attenuated neuropathic pain progression. Alternatively, overexpression of PKIA-AS1 was sufficient to induce neuropathic pain-like symptoms in uninjured rats. We also found that PKIA-AS1 mediated SNL-induced neuropathic pain by directly regulating the expression and function of CDK6, which is essential for the initiation and maintenance of neuroinflammation and neuropathic pain. Therefore, our study identifies PKIA-AS1 as a novel therapeutic target for neuroinflammation related neuropathic pain.

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Targeting cyclin D3/CDK6 activity for treatment of Parkinson's disease

Cited by 18 publications

References 53 publications

Panoramic Visualization of Circulating MicroRNAs Across Neurodegenerative Diseases in Humans

Panoramic Visualization of Circulating MicroRNAs Across Neurodegenerative Diseases in Humans

β-Elemene Reverses the Resistance of p53-Deficient Colorectal Cancer Cells to 5-Fluorouracil by Inducing Pro-death Autophagy and Cyclin D3-Dependent Cycle Arrest

Silencing of lncRNA PKIA-AS1 Attenuates Spinal Nerve Ligation-Induced Neuropathic Pain Through Epigenetic Downregulation of CDK6 Expression

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