scholarly journals CDC25B partners with PP2A to induce AMPK activation and tumor suppression in triple negative breast cancer

NAR Cancer ◽  
2020 ◽  
Vol 2 (4) ◽  
Author(s):  
Junmei Cairns ◽  
Reynold C Ly ◽  
Nifang Niu ◽  
Krishna R Kalari ◽  
Erin E Carlson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Xenograft Model ◽  
Direct Interaction ◽  
Ampk Activation ◽  
Dual Specificity ◽  
Phosphatase 2A ◽  
Dual Specificity Phosphatases ◽  
Amp Activated Protein Kinase ◽  
Protein Kinase Signaling

Abstract Cell division cycle 25 (CDC25) dual specificity phosphatases positively regulate the cell cycle by activating cyclin-dependent kinase/cyclin complexes. Here, we demonstrate that in addition to its role in cell cycle regulation, CDC25B functions as a regulator of protein phosphatase 2A (PP2A), a major cellular Ser/Thr phosphatase, through its direct interaction with PP2A catalytic subunit. Importantly, CDC25B alters the regulation of AMP-activated protein kinase signaling (AMPK) by PP2A, increasing AMPK activity by inhibiting PP2A to dephosphorylate AMPK. CDC25B depletion leads to metformin resistance by inhibiting metformin-induced AMPK activation. Furthermore, dual inhibition of CDC25B and PP2A further inhibits growth of 3D organoids isolated from patient derived xenograft model of breast cancer compared to CDC25B inhibition alone. Our study identifies CDC25B as a regulator of PP2A, and uncovers a mechanism of controlling the activity of a key energy metabolism marker, AMPK.

scholarly journals PIM kinases inhibit AMPK activation and promote tumorigenicity by phosphorylating LKB1

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Kwan Long Mung ◽  
William B. Eccleshall ◽  
Niina M. Santio ◽  
Adolfo Rivero-Müller ◽  
Päivi J. Koskinen
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Therapeutic Option ◽  
Xenograft Model ◽  
Site Directed Mutagenesis ◽  
Breast Cancer Cell Lines ◽  
Ampk Activation ◽  
Pim Kinases ◽  
Ampk Phosphorylation

Abstract Background The oncogenic PIM kinases and the tumor-suppressive LKB1 kinase have both been implicated in the regulation of cell growth and metabolism, albeit in opposite directions. Here we investigated whether these kinases interact with each other to influence AMPK activation and tumorigenic growth of prostate and breast cancer cells. Methods We first determined how PIM and LKB1 kinases affect AMPK phosphorylation levels. We then used in vitro kinase assays to demonstrate that LKB1 is phosphorylated by PIM kinases, and site-directed mutagenesis to identify the PIM target sites in LKB1. The cellular functions of PIM and LKB1 kinases were evaluated using either pan-PIM inhibitors or CRISPR/Cas9 genomic editing, with which all three PIM family members and/or LKB1 were knocked out from PC3 prostate and MCF7 breast cancer cell lines. In addition to cell proliferation assays, we examined the effects of PIM and/or LKB1 loss on tumor growth using the chick embryo chorioallantoic membrane (CAM) xenograft model. Results We provide both genetic and pharmacological evidence to demonstrate that inhibition of PIM expression or activity increases phosphorylation of AMPK at Thr172 in both PC3 and MCF7 cells, but not in their derivatives lacking LKB1. This is explained by our observation that all three PIM family kinases can phosphorylate LKB1 at Ser334. Wild-type LKB1, but not its phosphodeficient derivative, can restore PIM inhibitor-induced AMPK phosphorylation in LKB1 knock-out cells. In the CAM model, loss of LKB1 enhances tumorigenicity of PC3 xenografts, while cells lacking both LKB1 and PIMs exhibit slower proliferation rates and form smaller tumors. Conclusion PIM kinases are novel negative regulators of LKB1 that affect AMPK activity in an LKB1-dependent fashion. The impairment of cell proliferation and tumor growth in cells lacking both LKB1 and PIMs indicates that these kinases possess a shared signaling role in the context of cancer. These data also suggest that PIM inhibitors may be a rational therapeutic option for LKB1-deficient tumors.

scholarly journals DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress in triplenegative breast cancer

2019 ◽  
Author(s):  
Rita Moreno ◽  
Sourav Banerjee ◽  
Angus W. Jackson ◽  
Jean Quinn ◽  
Gregg Baillie ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Heat Shock ◽  
Cancer Progression ◽  
Xenograft Model ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Proteotoxic Stress ◽  
Dual Specificity ◽  
Stress Response Pathway ◽  
Nuclear Stability

SummaryTo survive aneuploidy-induced proteotoxic stress, cancer cells activate the proteotoxic-stress response pathway, which is controlled by heat shock factor 1 (HSF1). This pathway supports cancer initiation, cancer progression and chemoresistance and thus is an attractive target. As developing HSF1 inhibitors is challenging, the identification and targeting of upstream regulators of HSF1 presents a tractable alternative strategy. Here we demonstrate that in triple negative breast cancer (TNBC) cells, the dual-specificity tyrosine-regulated kinase 2 (DYRK2) phosphorylates HSF1, promoting its nuclear stability and transcriptional activity. Thus, DYRK2 depletion reduces HSF1 activity and sensitises TNBC cells to proteotoxic stress. Importantly, in tumours from TNBC patients, DYRK2 levels positively correlate with active HSF1 and associates with poor prognosis, suggesting that DYRK2 could be promoting TNBC. In agreement with this, DYRK2 depletion reduces tumour growth in a TNBC xenograft model. These findings identify DYRK2 as both, a key modulator of the HSF1 transcriptional program, and a potential therapeutic target.

scholarly journals Anti-tumor activity of BET inhibitors in androgen-receptor-expressing triple-negative breast cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
In Hae Park ◽  
Han Na Yang ◽  
Su Yeon Jeon ◽  
Jung-Ah Hwang ◽  
Min Kyeong Kim ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Androgen Receptor ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Xenograft Model ◽  
Bet Inhibitor ◽  
Bet Inhibitors ◽  
Anti Tumor Activity

Abstract Triple-negative breast cancer (TNBC) is a heterogeneous disease comprising several subtypes. Androgen-receptor (AR) signaling has been targeted by several investigational agents in luminal AR subtype TNBCs. Bromodomain (BRD) and extra-terminal motif (BET) protein inhibitors have been shown to attenuate AR signaling in metastatic castration-resistant prostate cancer and to overcome enzalutamide resistance. We demonstrated potent anti-tumor effects of the BET inhibitor JQ1 against AR-positive TNBC cell lines using cell viability and cell cycle analysis. To reveal the mechanisms of JQ1 effects, multiplex gene expression analysis and immunoblotting assays were used. We examined in vivo effects of JQ1 in a xenograft model of AR expressing TNBC. JQ1 exhibited its anti-proliferative activity by inducing apoptosis and cell cycle arrest. JQ1 activity was not mediated by MYC downregulation. Instead, JQ1 blocked the interactions among the ATPase-family AAA-domain-containing 2 protein (ATAD2), BRD2, BRD4, and AR; effectively suppressing the expression of AR associated targets. In addition, JQ1 showed significant anti-tumor activity in vivo in TNBC xenograft mouse models as a monotherapy and in combination with anti-AR therapy. Taken together, our results showed that the BET inhibitor JQ1 is a promising therapeutic agent for the treatment of AR-positive TNBC.

scholarly journals Expression Profile of Tyrosine Phosphatases in HER2 Breast Cancer Cells and Tumors

2010 ◽  
Vol 32 (5-6) ◽  
pp. 361-372
Author(s):  
Maria Antonietta Lucci ◽  
Rosaria Orlandi ◽  
Tiziana Triulzi ◽  
Elda Tagliabue ◽  
Andrea Balsari ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Differentially Expressed ◽  
Her2 Overexpression ◽  
Her2 Positive ◽  
Signalling Molecules ◽  
Her2 Breast Cancer ◽  
Dual Specificity ◽  
Dual Specificity Phosphatases ◽  
Therapy Target ◽  
In Cells

Background: HER2-overexpression promotes malignancy by modulating signalling molecules, which include PTPs/DSPs (protein tyrosine and dual-specificity phosphatases). Our aim was to identify PTPs/DSPs displaying HER2-associated expression alterations.Methods: HER2 activity was modulated in MDA-MB-453 cells and PTPs/DSPs expression was analysed with a DNA oligoarray, by RT-PCR and immunoblotting. Two public breast tumor datasets were analysed to identify PTPs/DSPs differentially expressed in HER2-positive tumors.Results: In cells (1) HER2-inhibition up-regulated 4 PTPs (PTPRA, PTPRK, PTPN11, PTPN18) and 11 DSPs (7 MKPs [MAP Kinase Phosphatases], 2 PTP4, 2 MTMRs [Myotubularin related phosphatases]) and down-regulated 7 DSPs (2 MKPs, 2 MTMRs, CDKN3, PTEN, CDC25C); (2) HER2-activation with EGF affected 10 DSPs (5 MKPs, 2 MTMRs, PTP4A1, CDKN3, CDC25B) and PTPN13; 8 DSPs were found in both groups. Furthermore, 7 PTPs/DSPs displayed also altered protein level. Analysis of 2 breast cancer datasets identified 6 differentially expressed DSPs: DUSP6, strongly up-regulated in both datasets; DUSP10 and CDC25B, up-regulated; PTP4A2, CDC14A and MTMR11 down-regulated in one dataset.Conclusions: Several DSPs, mainly MKPs and, unexpectedly, MTMRs, were altered following HER2-modulation in cells and 3 DSPs (DUSP6, CDC25B and MTMR11) were altered in both cells and tumors. Among these, DUSP6, strongly up-regulated in HER2-positive tumors, would deserve further investigation as tumor marker or potential therapy target.

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