The phosphatase PPM1A inhibits triple negative breast cancer growth by blocking cell cycle progression

Mazumdar, Abhijit; Tahaney, William M.; Bollu, Lakshmi Reddy; Poage, Graham M.; Hill, Jamal; Zhang, Yun; Mills, Gordon B.; Brown, Powel H.

doi:10.1038/s41523-019-0118-6

Cited by 22 publications

(19 citation statements)

References 44 publications

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“…Kim et al found that Vanicoside B inhibited the expression of CDK8-mediated signaling pathways and epithelial transforming proteins, and it induced cell-cycle arrest in MDA-MB-231 and HCC38 cells [153]. The protein phosphatase, Mg 2+/ Mn 2+ -dependent 1A (PPM1A), a member of Ser/Thr protein phosphatase 2C family, is involved in regulating proliferation, cell invasion, and migration through reducing CDK and RB phosphorylation in TNBC [154]. Yu et al found that the inhibition of the subunit of the COP9 signalosome complex subunit 4 (CSN4) increases the sub-G1 cell population and induces apoptosis via regulating CDK6 in the BC cell line MDA-MB-231 [155].…”

Section: The Novel Cdk Inhibitors In Bcmentioning

confidence: 99%

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

Ding

Cao

Lin

et al. 2020

IJMS

384

216

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Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose catalytic activities are regulated by interactions with cyclins and CDK inhibitors (CKIs). CDKs are key regulatory enzymes involved in cell proliferation through regulating cell-cycle checkpoints and transcriptional events in response to extracellular and intracellular signals. Not surprisingly, the dysregulation of CDKs is a hallmark of cancers, and inhibition of specific members is considered an attractive target in cancer therapy. In breast cancer (BC), dual CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, combined with other agents, were approved by the Food and Drug Administration (FDA) recently for the treatment of hormone receptor positive (HR+) advanced or metastatic breast cancer (A/MBC), as well as other sub-types of breast cancer. Furthermore, ongoing studies identified more selective CDK inhibitors as promising clinical targets. In this review, we focus on the roles of CDKs in driving cell-cycle progression, cell-cycle checkpoints, and transcriptional regulation, a highlight of dysregulated CDK activation in BC. We also discuss the most relevant CDK inhibitors currently in clinical BC trials, with special emphasis on CDK4/6 inhibitors used for the treatment of estrogen receptor-positive (ER+)/human epidermal growth factor 2-negative (HER2−) M/ABC patients, as well as more emerging precise therapeutic strategies, such as combination therapies and microRNA (miRNA) therapy.

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Section: The Novel Cdk Inhibitors In Bcmentioning

confidence: 99%

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

Ding

Cao

Lin

et al. 2020

IJMS

384

216

View full text Add to dashboard Cite

show abstract

“…Consequently, some of the responding productions such as Snail, connective tissue growth factor and matrix metalloproteinases would be released and further result in EMT ( 25 ). PPM1A is a phosphatase of the serine/threonine PPM family and the main substrates of PPM1A include MAPK, Smad2 and Smad3 and MKKs ( 12 – 14 ). PPM1A serves an important role in the signal transduction of TGF-β/Smad signaling and can inactivate TGF-β/Smad signaling by dephosphorylating Smad2/3 ( 26 , 27 ) ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Protein phosphatase Mg 2+ /Mn 2+ -dependent 1A (PPM1A) serves an important role in the signal transduction of TGF-β/Smad signaling and can inactivate TGF-β/Smad signaling by dephosphorylating Smad2/3. PPM1A functions as a tumor suppressor in bladder and breast cancer via regulating cell invasion, EMT and cell cycle progression ( 12 – 14 ). As part of a continuing study on the molecular mechanisms of JMSD, the present study further examined the role of PPM1A in the anti-EMT activity of JMSD on AECs.…”

Section: Introductionmentioning

confidence: 99%

PPM1A as a key target of the application of Jiawei‑Maxing‑Shigan decoction for the attenuation of radiation‑induced epithelial‑mesenchymal transition in type II alveolar epithelial cells

Lin

et al. 2021

Mol Med Rep

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Radiation-induced lung tissue injury is an important reason for the limited application of radiotherapy on thoracic malignancies. Previously, we reported that administration of Jiawei-Maxing-Shigan decoction (JMSD) attenuated the radiation-induced epithelial-mesenchymal transition (EMT) in alveolar epithelial cells (AECs) via TGF-β/Smad signaling. The present study aimed to examine the role of protein phosphatase Mg 2+ /Mn 2+ -dependent 1A (PPM1A) in the anti-EMT activity of JMSD on AECs. The components in the aqueous extract of JMSD were identified by high-performance liquid chromatography coupled with electrospray mass spectrometry. Primary rat type II AECs were treated with radiation (60Co γ-ray at 8 Gy) and JMSD-medicated serum. PPM1A was overexpressed and knocked down in the AECs via lentivirus transduction and the effects of JMSD administration on the key proteins related to TGF-β1/Smad signaling were measured by western blotting. It was found that radiation decreased the PPM1A expression in the AECs and JMSD-medicated serum upregulated the PPM1A expressions in the radiation-induced AECs. PPM1A overexpression increased the E-cadherin level but decreased the phosphorylated (p-)Smad2/3, vimentin and α-smooth muscle actin (α-SMA) levels in the AECs. By contrast, the PPM1A knockdown decreased the E-cadherin level and increased the p-Smad2/3, vimentin and α-SMA levels in the AECs and these effects could be blocked by SB431542 (TGF-β1/Smad signaling inhibitor). JMSD administration increased the E-cadherin level and decreased the p-Smad2/3, vimentin and α-SMA levels in the AECs; however, these effects could be blocked by siPPM1A-2. In conclusion, PPM1A is a key target of JMSD administration for the attenuation of the radiation-induced EMT in primary type II AECs via the TGF-β1/Smad pathway.

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“…Clinically, ER status is usually assessed by immunohistochemical staining to assess protein expression. Currently, selective estrogen receptor modulators and aromatase inhibitors are used alone, or in combination with chemotherapy to treat ER-positive BRCA, which can significantly improve the survival rate of estrogen receptor-positive BRCA patients ( Mazumdar et al, 2019 ). However, the resistance to endocrine therapy drugs hinders the clinical treatment of ER-positive BRCA, and new endocrine therapy drugs need to be explored to overcome this challenge.…”

Section: Introductionmentioning

confidence: 99%

Cryptotanshinone Is a Intervention for ER-Positive Breast Cancer: An Integrated Approach to the Study of Natural Product Intervention Mechanisms

Gao

Liang

et al. 2021

Front. Pharmacol.

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Background: Resistance to endocrine therapy has hampered clinical treatment in patients with ER-positive breast cancer (BRCA). Studies have confirmed that cryptotanshinone (CPT) has cytotoxic effects on BRCA cells and can significantly inhibit the proliferation and metastasis of ER-positive cancer cells.Methods: We analyzed the gene high-throughput data of ER-positive and negative BRCA to screen out key gene targets for ER-positive BRCA. Finally, the effects of CPT on BRCA cells (MCF-7 and MDA-MB-231) were examined, and quantitative RT-PCR was used to evaluate the expression of the key targets during CPT intervention.Results: A total of 169 differentially expressed genes were identified, and revealed that CPT affects the ER-positive BRCA cells by regulating CDK1, CCNA2, and ESR1. The overall experimental results initially show that MCF-7 cells were more sensitive to CPT than MDA-MB-231 cells, and the expression of ESR1 was not affected in the BRCA cells during CPT intervention, while the expression of CDK1 and CCNA2 were significantly down-regulated.Conclusion: CPT can inhibit the proliferation and migration of BRCA cells by regulating CDK1, CCNA2, and ESR1, especially in ER-positive BRCA samples. On the one hand, our research has discovered the possible mechanism that CPT can better interfere with ER+ BRCA; on the other hand, the combination of high-throughput data analysis and network pharmacology provides valuable information for identifying the mechanism of drug intervention in the disease.

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The phosphatase PPM1A inhibits triple negative breast cancer growth by blocking cell cycle progression

Cited by 22 publications

References 44 publications

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

PPM1A as a key target of the application of Jiawei‑Maxing‑Shigan decoction for the attenuation of radiation‑induced epithelial‑mesenchymal transition in type II alveolar epithelial cells

Cryptotanshinone Is a Intervention for ER-Positive Breast Cancer: An Integrated Approach to the Study of Natural Product Intervention Mechanisms

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