Not So Fast: Cultivating miRs as Kinks in the Chain of the Cell Cycle

Schiewer, Matthew J.; Knudsen, Karen E.

doi:10.1016/j.ccell.2017.03.012

Cited by 6 publications

(6 citation statements)

References 11 publications

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“…We showed that TBX15 levels were correlated with miR-152 expression levels in breast cancer tissues using bioinformatics analysis. Recently, several miRNAs were found to effectively suppress chemoresistance in cancer cells [32,33]. Recent studies by our group showed that miR-152 overexpression sensitized cisplatin-resistant ovarian cancer cells [24].…”

Section: Discussionmentioning

confidence: 99%

TBX15/miR-152/KIF2C Pathway Regulates Breast Cancer Doxorubicin Resistance Via Promoting PKM2 Ubiquitination

Jiang

Xie

Qian

et al. 2021

Preprint

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Background: Chemoresistance is a critical risk problem for breast cancer treatment. However, mechanisms by which chemoresistance arises remains to be elucidated. The expression of T-box transcription factor 15 (TBX-15) was found downregulated in some cancer tissues. However, role and mechanism of TBX15 in breast cancer chemoresistance is unknown. Here we aimed to identify the effects and mechanisms of TBX15 in doxorubicin resistance in breast cancer.Methods: As measures of Drug sensitivity analysis, MTT and IC50 assays were used in DOX-resistant breast cancer cells. ECAR and OCR assays were used to analyze the glycolysis level, while Immunoblotting and Immunofluorescence assays were used to analyze the autophagy levels in vitro. By using online prediction software, luciferase reporter assays, co-Immunoprecipitation, Western blotting analysis and experimental animals models, we further elucidated the mechanisms.Results: We found TBX15 expression levels were decreased in Doxorubicin (DOX)-resistant breast cancer cells. Overexpression of TBX15 reversed the DOX resistance by inducing microRNA-152 (miR-152) expression. We found that KIF2C levels were highly expressed in DOX-resistant breast cancer tissues and cells, and KIF2C was a potential target of miR-152. TBX15 and miR-152 overexpression suppressed autophagy and glycolysis in breast cancer cells, while KIF2C overexpression reversed the process. Overexpression of KIF2C increased DOX resistance in cancer cells. Furthermore, KIF2C directly binds with PKM2 for inducing the DOX resistance. KIF2C can prevent the ubiquitination of PKM2 and increase its protein stability. In addition, we further identified that Domain-2 of KIF2C played a major role in the binding with PKM2 and preventing PKM2 ubiquitination, which enhanced DOX resistance by promoting autophagy and glycolysis. Conclusions: Our data identify a new mechanism by which TBX15 abolishes DOX chemoresistance in breast cancer, and suggest that TBX15/miR-152/KIF2C axis is a novel signaling pathway for mediating DOX resistance in breast cancer through regulating PKM2 ubiquitination and decreasing PKM2 stability. This finding suggests new therapeutic target and/or novel strategy development for cancer treatment to overcome drug resistance in the future.

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Section: Discussionmentioning

confidence: 99%

TBX15/miR-152/KIF2C Pathway Regulates Breast Cancer Doxorubicin Resistance Via Promoting PKM2 Ubiquitination

Jiang

Xie

Qian

et al. 2021

Preprint

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“…The MYC/CDK2/SKP2/p27 axis could also be therapeutically exploited on the RNA-level. One of us demonstrated recently that in vivo administration of microRNAs evolutionarily enriched to target multiple cyclins/CDKs, including cyclin E and CDK2, efficiently blunts the progression of patient-derived, treatment-refractory triple negative/basal breast cancers without detectable animal toxicity [ 251 , 252 ]. Another potential strategy is inhibition of cellular PP2A inhibitors using SET antagonist peptides, thereby reducing Ser-62 phosphorylation and MYC stability [ 253 ].…”

Section: Targeting the Myc/cdk2/skp2/p27 Axis In Cancermentioning

confidence: 99%

MYC Modulation around the CDK2/p27/SKP2 Axis

Hydbring

Castell

Larsson

2017

Genes

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MYC is a pleiotropic transcription factor that controls a number of fundamental cellular processes required for the proliferation and survival of normal and malignant cells, including the cell cycle. MYC interacts with several central cell cycle regulators that control the balance between cell cycle progression and temporary or permanent cell cycle arrest (cellular senescence). Among these are the cyclin E/A/cyclin-dependent kinase 2 (CDK2) complexes, the CDK inhibitor p27KIP1 (p27) and the E3 ubiquitin ligase component S-phase kinase-associated protein 2 (SKP2), which control each other by forming a triangular network. MYC is engaged in bidirectional crosstalk with each of these players; while MYC regulates their expression and/or activity, these factors in turn modulate MYC through protein interactions and post-translational modifications including phosphorylation and ubiquitylation, impacting on MYC’s transcriptional output on genes involved in cell cycle progression and senescence. Here we elaborate on these network interactions with MYC and their impact on transcription, cell cycle, replication and stress signaling, and on the role of other players interconnected to this network, such as CDK1, the retinoblastoma protein (pRB), protein phosphatase 2A (PP2A), the F-box proteins FBXW7 and FBXO28, the RAS oncoprotein and the ubiquitin/proteasome system. Finally, we describe how the MYC/CDK2/p27/SKP2 axis impacts on tumor development and discuss possible ways to interfere therapeutically with this system to improve cancer treatment.

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“…Sustaining proliferative signaling is one of the hallmarks of cancer (Hanahan and Weinberg, 2011). The unbridled cell proliferation of cancer cells is often manifested by alterations of cell cycle progression; targeting cell‐cycle regulation represents an attractive anti‐cancer therapeutic strategy (Schiewer and Knudsen, 2017). Cyclin D1, one of the ultimate recipients of ERK pathway, drives progression through the G1 phase and promotes proliferation by binding and activating CDK4 and CDK6 (Brakebusch et al, 2002; Musgrove et al, 2011; Sen et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Krill Oil Perturbs Proliferation and Migration of Mouse Colon Cancer Cells in vitro by Impeding Extracellular Signal‐Regulated Protein Kinase Signaling Pathway

Jing

Wang

et al. 2020

Lipids

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The prevalence of colorectal cancer (CRC) continues to increase. Treatment of CRC remains a significant clinical challenge, and effective therapies for advanced CRC are desperately needed. Increasing attention and ongoing research efforts have focused on krill oil that may provide health benefits to the human body. Here we report that krill oil exerts in vitro anticancer activity through a direct inhibition on proliferation, colony formation, migration, and invasion of mouse colon cancer cells. Krill oil inhibited the proliferation and colony formation of CT‐26 colon cancer cells by causing G0/G1 cell cycle arrest and apoptosis. Cell cycle arrest was attributable to reduction of cyclin D1 levels in krill oil‐treated cells. Further studies revealed that krill oil induced mitochondrial‐dependent apoptosis of CT‐26 cells, including loss of mitochondrial membrane potential, increased cytosolic calcium levels, activation of caspase‐3, and downregulation of anti‐apoptotic proteins MCL‐1 and BCL‐XL. Krill oil suppressed migration of CT‐26 cells by disrupting the microfilaments and microtubules. Extracellular signal‐regulated protein kinase (ERK) plays crucial roles in regulating proliferation and migration of cancer cells. We found that krill oil attenuated the activation of ERK signaling pathway to exert the effects on cell cycle, apoptosis, and migration of colon cancer cells. We speculate that polyunsaturated fatty acids of krill oil may dampen ERK activation by decreasing the phospholipid saturation of cell membrane. Although findings from in vitro studies may not necessarily translate in vivo, our study provides insights into the possibility that krill oil or its components could have therapeutic potential in colon cancer.

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Not So Fast: Cultivating miRs as Kinks in the Chain of the Cell Cycle

Cited by 6 publications

References 11 publications

TBX15/miR-152/KIF2C Pathway Regulates Breast Cancer Doxorubicin Resistance Via Promoting PKM2 Ubiquitination

TBX15/miR-152/KIF2C Pathway Regulates Breast Cancer Doxorubicin Resistance Via Promoting PKM2 Ubiquitination

MYC Modulation around the CDK2/p27/SKP2 Axis

Krill Oil Perturbs Proliferation and Migration of Mouse Colon Cancer Cells in vitro by Impeding Extracellular Signal‐Regulated Protein Kinase Signaling Pathway

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