scholarly journals Trichostatin A Suppresses EGFR Expression through Induction of MicroRNA-7 in an HDAC-Independent Manner in Lapatinib-Treated Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Chih-Yen Tu ◽  
Chia-Hung Chen ◽  
Te-Chun Hsia ◽  
Min-Hsiang Hsu ◽  
Ya-Ling Wei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Kinase Inhibitor ◽  
Trichostatin A ◽  
Her2 Positive ◽  
Independent Manner ◽  
Dual Inhibitor ◽  
Egfr Expression

Lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, has been shown to improve the survival rate of patients with advanced HER2-positive breast cancers. However, the off-target activity of lapatinib in inducing EGFR expression without tyrosine kinase activity was demonstrated to render HER2-negative breast cancer cells more metastatic, suggesting a limitation to the therapeutic effectiveness of this dual inhibitor in HER2-heterogeneous tumors. Therefore, targeting EGFR expression may be a feasible approach to improve the anticancer efficiency of lapatinib-based therapy. Inhibition of HDAC has been previously reported to epigenetically suppress EGFR protein expression. In this study, however, our data indicated that treatment with HDAC inhibitors trichostatin A (TSA), but not suberoylanilide hydroxamic acid (SAHA) or HDAC siRNA, can attenuate both protein and mRNA expressions of EGFR in lapatinib-treated triple-negative breast cancer cells, suggesting that TSA may suppress EGFR expression independently of HDAC inhibition. Nevertheless, TSA reduced EGFR 3′UTR activity and induced the gene expression of microRNA-7, a known EGFR-targeting microRNA. Furthermore, treatment with microRNA-7 inhibitor attenuated TSA-mediated EGFR suppression. These results suggest that TSA induced microRNA-7 expression to downregulate EGFR expression in an HDAC-independent manner.

scholarly journals HER2-Targeted Tyrosine Kinase Inhibitors Cause Therapy-Induced-Senescence in Breast Cancer Cells

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 197 ◽  
Author(s):  
Martina S.J. McDermott ◽  
Neil Conlon ◽  
Brigid C. Browne ◽  
Adam Szabo ◽  
Naoise C. Synnott ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Fate ◽  
Breast Cancer Cells ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Prolonged Treatment ◽  
Her2 Positive

Prolonged treatment of HER2 positive breast cancer cells with tyrosine kinase inhibitors (TKIs) leads to the emergence of acquired resistance. However, the effects of continuous TKI exposure on cell fate, and the steps leading to the acquisition of a resistant phenotype are poorly understood. To explore this, we exposed five HER2 positive cells lines to HER2 targeted therapies for periods of up to 4 weeks and examined senescence associated β-galactosidase (SA-β-gal) activity together with additional markers of senescence. We found that lapatinib treatment resulted in phenotypic alterations consistent with a senescent phenotype and strong SA-β-gal activity in HER2-positive cell lines. Lapatinib-induced senescence was associated with elevated levels of p15 and p27 but was not dependent on the expression of p16 or p21. Restoring wild type p53 activity either by transfection or by treatment with APR-246, a molecule which reactivates mutant p53, blocked lapatinib-induced senescence and caused increased cell death. In contrast to lapatinib, SA-β-gal activity was not induced by exposing the cells to trastuzumab as a single agent but co-administration of lapatinib and trastuzumab induced senescence, as did treatment of the cells with the irreversible HER2 TKIs neratinib and afatinib. Neratinib- and afatinib-induced senescence was not reversed by removing the drug whereas lapatinib-induced senescence was reversible. In summary, therapy-induced senescence represents a novel mechanism of action of HER2 targeting agents and may be a potential pathway for the emergence of resistance.

scholarly journals Targeting the EphB4 receptor tyrosine kinase sensitizes HER2-positive breast cancer cells to Lapatinib

2020 ◽  
Vol 475 ◽  
pp. 53-64 ◽  
Author(s):  
Jinlei Ding ◽  
Yating Yao ◽  
Gena Huang ◽  
Xiaonan Wang ◽  
Jingyan Yi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Receptor Tyrosine Kinase ◽  
Breast Cancer Cells ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

scholarly journals ErbB1/2 tyrosine kinase inhibitor mediates oxidative stress-induced apoptosis in inflammatory breast cancer cells

2011 ◽  
Vol 132 (1) ◽  
pp. 109-119 ◽  
Author(s):  
Katherine M. Aird ◽  
Jennifer L. Allensworth ◽  
Ines Batinic-Haberle ◽  
H. Kim Lyerly ◽  
Mark W. Dewhirst ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cancer Cells ◽  
Inflammatory Breast Cancer ◽  
Breast Cancer Cells ◽  
Kinase Inhibitor ◽  
Induced Apoptosis

scholarly journals A targeted enzyme approach to sensitization of tyrosine kinase inhibitor-resistant breast cancer cells

2012 ◽  
Vol 318 (16) ◽  
pp. 2014-2021 ◽  
Author(s):  
Courtney R. Giordano ◽  
Kelly L. Mueller ◽  
Laura J. Terlecky ◽  
Kendra A. Krentz ◽  
Aliccia Bollig-Fischer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Kinase Inhibitor

scholarly journals Astemizole, an Inhibitor of Ether-�-Go-Go-1 Potassium Channel, Increases the Activity of the Tyrosine Kinase Inhibitor Gefitinib in Breast Cancer Cells

2019 ◽  
Vol 71 (3) ◽  
Author(s):  
Janice García-Quiroz ◽  
María E. González-González ◽  
Lorena Díaz ◽  
David Ordaz-Rosado ◽  
Mariana Segovia-Mendoza ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Potassium Channel ◽  
Tyrosine Kinase Inhibitor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Kinase Inhibitor

scholarly journals ERRα activates SHMT2 transcription to enhance the resistance of breast cancer to lapatinib via modulating the mitochondrial metabolic adaption

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Xin Li ◽  
Kejing Zhang ◽  
Yu Hu ◽  
Na Luo
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Transcription Initiation ◽  
Promoter Region ◽  
Breast Cancer Cells ◽  
Kinase Inhibitor ◽  
Cancer Resistance ◽  
Her2 Positive ◽  
Protein Levels ◽  
Lapatinib Treatment

Abstract Lapatinib, a tyrosine kinase inhibitor, can initially benefit the patients with breast tumors but fails in later treatment due to the inevitable development of drug resistance. Estrogen-related receptor α (ERRα) modulates the metabolic adaptations in lapatinib-resistant cancer cells; however, the underlying mechanism remains unclear. ERRα was predicted to bind to the serine hydroxymethyltransferase 2 (SHMT2) transcription initiation site in the ER- and HER2-positive cell line BT-474; thus, we hypothesize that ERRα might modulate the resistance of breast cancer to lapatinib via regulating SHMT2. In the present study, we revealed that 2.5 and 5 µM lapatinib treatment could significantly decrease the expression and protein levels of ERRα and SHMT2; ERRα and SHMT2 expression and protein levels were significantly up-regulated in breast cancer cells, in particularly in breast cancer cells with resistance to lapatinib. ERRα knockdown restored the inhibitory effects of lapatinib on the BT-474R cell viability and migration; in the meantime, ERRα knockdown rescued the production of reactive oxygen species (ROS) whereas decreased the ratio of glutathione (GSH)/oxidized glutathione (GSSG) upon lapatinib treatment. Via targeting SHMT2 promoter region, ERRα activated the transcription of SHMT2. The effects of ERRα knockdown on BT-474R cells under lapatinib treatment could be significantly reversed by SHMT2 overexpression. In conclusion, ERRα knockdown suppresses the detoxification and the mitochondrial metabolic adaption in breast cancer resistant to lapatinib; ERRα activates SHMT2 transcription via targeting its promoter region, therefore enhancing breast cancer resistance to lapatinib.

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