scholarly journals Elevated SGK1 predicts resistance of breast cancer cells to Akt inhibitors

2013 ◽  
Vol 452 (3) ◽  
pp. 499-508 ◽  
Author(s):  
Eeva M. Sommer ◽  
Hannah Dry ◽  
Darren Cross ◽  
Sylvie Guichard ◽  
Barry R. Davies ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Therapeutic Potential ◽  
Mammalian Target Of Rapamycin ◽  
Akt Inhibitor ◽  
Resistant Lines ◽  
Phosphoinositide 3 Kinase ◽  
Resistant Cells

The majority of human cancers harbour mutations promoting activation of the Akt protein kinase, and Akt inhibitors are being evaluated in clinical trials. An important question concerns the understanding of the innate mechanisms that confer resistance of tumour cells to Akt inhibitors. SGK (serum- and glucocorticoid-regulated kinase) is closely related to Akt and controlled by identical upstream regulators {PI3K (phosphoinositide 3-kinase), PDK1 (phosphoinositide-dependent kinase 1) and mTORC2 [mTOR (mammalian target of rapamycin) complex 2]}. Mutations that trigger activation of Akt would also stimulate SGK. Moreover, Akt and SGK possess analogous substrate specificities and are likely to phosphorylate overlapping substrates to promote proliferation. To investigate whether cancers possessing high SGK activity could possess innate resistance to Akt-specific inhibitors (that do not target SGK), we analysed SGK levels and sensitivity of a panel of breast cancer cells towards two distinct Akt inhibitors currently in clinical trials (AZD5363 and MK-2206). This revealed a number of Akt-inhibitor-resistant lines displaying markedly elevated SGK1 that also exhibited significant phosphorylation of the SGK1 substrate NDRG1 [N-Myc (neuroblastoma-derived Myc) downstream-regulated gene 1]. In contrast, most Akt-inhibitor-sensitive cell lines displayed low/undetectable levels of SGK1. Intriguingly, despite low SGK1 levels, several Akt-inhibitor-sensitive cells showed marked NDRG1 phosphorylation that was, unlike in the resistant cells, suppressed by Akt inhibitors. SGK1 knockdown markedly reduced proliferation of Akt-inhibitor-resistant, but not -sensitive, cells. Furthermore, treatment of Akt-inhibitor-resistant cells with an mTOR inhibitor suppressed proliferation and led to inhibition of SGK1. The results of the present study suggest that monitoring SGK1 levels as well as responses of NDRG1 phosphorylation to Akt inhibitor administration could have a use in predicting the sensitivity of tumours to compounds that target Akt. Our findings highlight the therapeutic potential that SGK inhibitors or dual Akt/SGK inhibitors might have for treatment of cancers displaying elevated SGK activity.

New anti-cancer role for PDK1 inhibitors: preventing resistance to tamoxifen

2008 ◽  
Vol 417 (1) ◽  
pp. e5-e7 ◽  
Author(s):  
Christian Peifer ◽  
Dario R. Alessi
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Acquired Resistance ◽  
Mammalian Target Of Rapamycin ◽  
Signal Transduction Pathway ◽  
Cancer Treatments ◽  
Biochemical Journal ◽  
Anti Cancer ◽  
Phosphoinositide 3 Kinase

Tamoxifen is one of the most prescribed anti-breast-cancer drugs, but tumours becoming resistant hinder its efficacy in the clinic. There is therefore great interest in developing strategies to reduce resistance and sensitize breast cancer cells to tamoxifen. A groundbreaking study by Iorns et al. published in this issue of the Biochemical Journal suggests that a signal transduction pathway controlled by PDK1 (phosphoinositide-dependent kinase 1) plays a crucial role in regulating the sensitivity of breast cancer cells to tamoxifen. The implications of this study are that PDK1 or PI3K (phosphoinositide 3-kinase), Akt (also known as protein kinase B), S6K (S6 kinase) and mTOR (mammalian target of rapamycin) inhibitors, already being developed for cancer therapy, are likely to have additional utility in sensitizing breast tumours to tamoxifen. In this commentary we also discuss the possibility that inhibiting the PDK1 pathway may help overcome acquired resistance to other anti-cancer treatments.

scholarly journals Integrin α3β1 Promotes Invasive and Metastatic Properties of Breast Cancer Cells through Induction of the Brn-2 Transcription Factor

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 480
Author(s):  
Rakshitha Pandulal Miskin ◽  
Janine S. A. Warren ◽  
Abibatou Ndoye ◽  
Lei Wu ◽  
John M. Lamar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Cancer Cells ◽  
Cell Invasion ◽  
Breast Cancer Cells ◽  
Gene Promoter ◽  
Akt Inhibitor ◽  
Integrin Α3β1

In the current study, we demonstrate that integrin α3β1 promotes invasive and metastatic traits of triple-negative breast cancer (TNBC) cells through induction of the transcription factor, Brain-2 (Brn-2). We show that RNAi-mediated suppression of α3β1 in MDA-MB-231 cells caused reduced expression of Brn-2 mRNA and protein and reduced activity of the BRN2 gene promoter. In addition, RNAi-targeting of Brn-2 in MDA-MB-231 cells decreased invasion in vitro and lung colonization in vivo, and exogenous Brn-2 expression partially restored invasion to cells in which α3β1 was suppressed. α3β1 promoted phosphorylation of Akt in MDA-MB-231 cells, and treatment of these cells with a pharmacological Akt inhibitor (MK-2206) reduced both Brn-2 expression and cell invasion, indicating that α3β1-Akt signaling contributes to Brn-2 induction. Analysis of RNAseq data from patients with invasive breast carcinoma revealed that high BRN2 expression correlates with poor survival. Moreover, high BRN2 expression positively correlates with high ITGA3 expression in basal-like breast cancer, which is consistent with our experimental findings that α3β1 induces Brn-2 in TNBC cells. Together, our study demonstrates a pro-invasive/pro-metastatic role for Brn-2 in breast cancer cells and identifies a role for integrin α3β1 in regulating Brn-2 expression, thereby revealing a novel mechanism of integrin-dependent breast cancer cell invasion.

Targeting the phosphoinositide 3-kinase/AKT pathways by small molecules and natural compounds as a therapeutic approach for breast cancer cells

2019 ◽  
Vol 46 (5) ◽  
pp. 4809-4816 ◽  
Author(s):  
Amin Soltani ◽  
Samira Torki ◽  
Milad Sabzevary Ghahfarokhi ◽  
Mohammad Saied Jami ◽  
Mahdi Ghatrehsamani
Keyword(s):  
Breast Cancer ◽  
Small Molecules ◽  
Cancer Cells ◽  
Therapeutic Approach ◽  
Breast Cancer Cells ◽  
Natural Compounds ◽  
Phosphoinositide 3 Kinase

scholarly journals Overexpression of Extradomain-B Fibronectin is Associated with Invasion of Breast Cancer Cells

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1826
Author(s):  
Amita Vaidya ◽  
Helen Wang ◽  
Victoria Qian ◽  
Hannah Gilmore ◽  
Zheng-Rong Lu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Clonal Evolution ◽  
Clinical Samples ◽  
Cell Populations ◽  
Akt Inhibitor ◽  
Poor Overall Survival ◽  
Critical Function ◽  
Invasive Cell

Breast tumor heterogeneity is a major impediment to oncotherapy. Cancer cells undergo rapid clonal evolution, thereby acquiring significant growth and invasive advantages. The absence of specific markers of these high-risk populations precludes efficient therapeutic and diagnostic management of the disease. Given the critical function of tumor microenvironment in the oncogenic circuitry, we sought to determine the expression profile of the extracellular matrix oncoprotein, extradomain-B fibronectin (EDB-FN) in invasive breast cancer. Analyses of TCGA/GTEx databases and immunostaining of clinical samples found a significant overexpression of EDB-FN in breast tumors, which correlated with poor overall survival. Significant upregulation of EDB-FN was observed in invasive cell populations generated from relatively less invasive MCF7 and MDA-MB-468 cells by long-term TGF-β treatment and acquired chemoresistance. Treatment of the invasive cell populations with an AKT inhibitor (MK2206-HCl) reduced their invasive potential, with a concomitant decrease in their EDB-FN expression, partly through the phosphoAKT-SRp55 pathway. EDB-FN downregulation, with direct RNAi of EDB-FN or indirectly through RNAi of SRp55, also resulted in reduced motility of the invasive cell populations, validating the correlation between EDB-FN expression and invasion of breast cancer cells. These data establish EDB-FN as a promising molecular marker for non-invasive therapeutic surveillance of aggressive breast cancer.

scholarly journals Hyperoside Induces Breast Cancer Cells Apoptosis via ROS-Mediated NF-κB Signaling Pathway

2019 ◽  
Vol 21 (1) ◽  
pp. 131 ◽  
Author(s):  
Jinxia Qiu ◽  
Tao Zhang ◽  
Xinying Zhu ◽  
Chao Yang ◽  
Yaxing Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mouse Model ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Breast Cancer Cells ◽  
Caspase 3 ◽  
Therapeutic Potential ◽  
B Cell Lymphoma ◽  
Flavonoid Glycosides

Hyperoside (quercetin 3-o-β-d-galactopyranoside) is one of the flavonoid glycosides with anti-inflammatory, antidepressant, and anti-cancer effects. But it remains unknown whether it had effects on breast cancer. Here, different concentrations of hyperoside were used to explore its therapeutic potential in both breast cancer cells and subcutaneous homotransplant mouse model. CCK-8 and wound healing assays showed that the viability and migration capability of Michigan Cancer Foundation-7 (MCF-7) and 4T1 cells were inhibited by hyperoside, while the apoptosis of cells were increased. Real-time quantitative PCR (qRT-PCR) and western blot analysis were used to detect mRNA and the protein level, respectively, which showed decreased levels of B cell lymphoma-2 (Bcl-2) and X-linked inhibitor of apoptosis (XIAP), and increased levels of Bax and cleaved caspase-3. After exploration of the potential mechanism, we found that reactive oxygen species (ROS) production was reduced by the administration of hyperoside, which subsequently inhibited the activation of NF-κB signaling pathway. Tumor volume was significantly decreased in subcutaneous homotransplant mouse model in hyperoside-treated group, which was consistent with our study in vitro. These results indicated that hyperoside acted as an anticancer drug through ROS-related apoptosis and its mechanism included activation of the Bax–caspase-3 axis and the inhibition of the NF-κB signaling pathway.

C/EBPδ Modulates Cell Growth, Differentiation and Apoptosis of Myeloid Leukemia, Prostate and Breast Cancer Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4300-4300
Author(s):  
Sigal Gery ◽  
Sakae Stanosaki ◽  
Takayuki Ikezoe ◽  
Wolf K. Hofmann ◽  
Adrian F. Gombart ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Myeloid Leukemia ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Leukemic Cells ◽  
Granulocytic Differentiation ◽  
Mcf 7

Abstract C/EBPδ belongs to the family of highly conserved CCAAT/enhancer binding protein (C/EBP) transcription factors. Members of this family play a critical role in the regulation of mitotic growth arrest and differentiation in numerous cell types. To examine the consequences of C/EPBδ expression, we transfected C/EPBδ into CML myeloid leukemia (KCL22, K562), prostate (LNCaP, PC3, DU145), and breast (MCF-7, T47D, MDA-MB-231) cancer cell lines. C/EBPδ expression resulted in a proliferative arrest and an increase in apoptosis of the myeloid leukemia cells, as well as the prostate cells LNCaP and PC3, and the breast cells MCF-7 and T47D. In contrast, DU145 prostate and MDA-MB-231 breast cancer cells were not inhibited by C/EBPδ, indicating that the biologically properties of C/EBPδ depend upon its cellular context. We further studied the molecular mechanisms underlying the affect of C/EPBδ expression in CML leukemic cells. Myeloid differentiation of KCL22 and K562 blast cells as shown by morphologic changes and induction of secondary specific granule genes, occurred within 4 days of inducing expression of C/EBPδ. Furthermore, expression of C/EBPδ was associated with downregulation of c-Myc and cyclin E, and upregulation of the forkhead transcription factor FoxO1a (FKHR) and the cyclin-dependent kinase inhibitor p27Kip1. In addition, microarray analysis showed that C/EBPδ mRNA is upregulated during granulocytic differentiation of normal CD34+ bone marrow cells, suggesting that C/EBPδ is involved in lineage-specific differentiation. Taken together, these results show that expression of C/EBPδ in BCR-ABL-positive CML cells in blast crisis, is sufficient for neutrophil differentiation and suggest that ectopic induction of C/EBPδ in the blastic phase of CML, as well as in certain cases of prostate and breast cancers, may hold promising therapeutic potential.

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