The Tyrphostin B42 Inhibits Cell Proliferation and HER-2 Autophosphorylation in Cervical Carcinoma Cell Lines

Soto‐Cruz, Isabel; Rangel-Corona, Rosalva; Valle‐Mendiola, Arturo; Moreno-Morales, Xóchitl; Santiago-Pérez, Rocío; Weiss‐Steider, Benny; Cáceres‐Cortés, Julio Roberto

doi:10.1080/07357900701561099

Cited by 6 publications

(12 citation statements)

References 29 publications

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“…Tyrphostin B42 (AG490) is an inhibitor of epidermal growth factor receptor (EGFR) by competing to binding sites with receptor tyrosine kinases (RTKs) (35). Tyrphostin B42 has been reported to have an inhibitory effect on the proliferation of many tumor cells through IL-6/JAK2/STAT3 signaling (22)(23)(24). A previous study revealed that in vitro AG-490 (60-100 µM) blocked the constitutive activation of Stat3 sm , and inhibited spontaneous as well as interleukin 2-induced growth of mycosis fungoides tumor cells (36).…”

Section: Discusssionmentioning

confidence: 99%

“…In the present study, we first investigated the activity of IL-6/JAK2/STAT3 signaling in patients with pancreatic cancer and in PCCs with (PANC-1-TSA) or without (PANC-1) TSA resistance. Secondly, tyrphostin B42 had been reported to possess inhibitory activity on the proliferation of various tumor cells (22,23), and to be associated with IL-6/JAK2/STAT3 signaling (24). Therefore, in the present study the effects of tyrphostin B42 on TSA-induced over-proliferation and resistance of PCCs were also evaluated.…”

Section: Introductionmentioning

confidence: 95%

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Tyrphostin B42 attenuates trichostatin A-mediated resistance in pancreatic cancer cells by antagonizing IL-6/JAK2/STAT3 signaling

Zhang

Hong

et al. 2018

Oncol Rep

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Drug-resistance is the key reason for the ineffectiveness of chemotherapy in pancreatic cancer. Thus, it is very important to explore the molecular mechanisms of drug‑resistance and the methods of effective intervention. In the present study, we investigated the effect of tyrphostin B42, also called AG490, on histone deacetylase (HDAC) inhibitor trichostatin A (TSA)‑induced resistance in pancreatic cancer cells (PCCs). Evidence from phase contrast microscope revealed that TSA‑resistant cells (PANC‑1‑TSA) had higher proliferative activity than non‑resistant cells (PANC‑1). This over‑proliferative activity induced by TSA may be associated with abnormal activation of JAK2/STAT3 signaling, which can be strengthened by interleukin‑6 (IL‑6), a STAT3‑upstream inducer, resulting in enhanced expression of STAT3-downstream target genes including c‑Myc, c‑Src, HIF‑1α, and CCND1. In addition, increased expression of Bcl‑2 mRNA and decreased expression of Bax mRNA in PANC‑1‑TSA cells indicated that TSA induced the inhibition of mitochondrial-dependent apoptosis in PCCs. Tyrphostin B42 treatment evidently antagonized the activation of IL‑6/JAK2/STAT3 in a dose‑dependent manner. As a result, tyrphostin B42 inhibited the over‑proliferative activity of PANC‑1‑TSA cells, and downregulated the expression of IL‑6/JAK2/STAT3‑downstream target genes. Moreover, tyrphostin B42 induced the apoptosis of PCCs by regulating the expression of mitochondrial‑related genes. Therefore, these findings demonstrated that tyrphostin B42 attenuated TSA‑mediated resistance in PCCs by antagonizing the IL‑6/JAK2/STAT3 signaling.

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Section: Discusssionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Tyrphostin B42 attenuates trichostatin A-mediated resistance in pancreatic cancer cells by antagonizing IL-6/JAK2/STAT3 signaling

Zhang

Hong

et al. 2018

Oncol Rep

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“…This type of cancer has been reported to express a variety of molecules, some of which are associated with the progression of HPV-associated cervical cancer, such as STAT5A [ 70 ], hypoxia-inducible factor 1 α (HIF-1 α ), and glucose transport protein 1 (GLUT1) [ 71 ]. Other molecules reported to be present in cervical cancer cells include c-Kit, HER2 [ 72 , 73 ], JAK3, STAT5 [ 12 , 64 ], JAK1 [ 64 ], MICA, MICB, NKG2D [ 74 ], HER3 (Zerecero-Carreon, unpublished data), STAT3, Syk, and Lck (unpublished data).…”

Section: Il-2 Expression and Signalling In Cervical Cancer Cellsmentioning

confidence: 99%

Pleiotropic Effects of IL-2 on Cancer: Its Role in Cervical Cancer

Valle‐Mendiola¹,

Gutiérrez‐Hoya

Lagunas-Cruz³

et al. 2016

Mediators of Inflammation

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IL-2 receptor (IL-2R) signalling is critical for normal lymphocyte proliferation, but its role in cervical cancer is not fully understood. The receptor is composed of three chains: IL-2α, IL-2β, and IL-2γ. Intracellular signalling is initiated by ligand-induced heterodimerization of the IL-2β and IL-2γ chains, resulting in the activation of multiple intracellular kinases. Recently, IL-2R was shown to be expressed on nonhaematopoietic cells, especially on several types of tumour cells. However, the function of this receptor on malignant cells has not been clearly defined. The expression of IL-2R and the production of IL-2 in cervical cancer cells have been documented as well as expression of molecules of the JAK-STAT pathway. In the current review we have highlighted the differences in the responses of molecules downstream from the IL-2R in normal lymphocytes and tumour cells that could explain the presence of tumour cells in an environment in which cytotoxic lymphocytes also exist and compete and also the effect of different concentrations of IL-2 that could activate effector cells of the immune system cells, which favour the elimination of tumour cells, or concentrations that may promote a regulatory microenvironment in which tumour cells can easily grow.

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“…Our previous research demonstrated that the EGFR was not phosphorylated in the CALO and INBL cervical cancer cell lines (19). Since the receptor was not phosphorylated we hypothesized that it was a dead kinase due to the presence of inactivating mutations.…”

Section: Introductionmentioning

confidence: 93%

Mutations in the helix αC of the catalytic domain from the EGFR affect its activity in cervical cancer cell lines

et al. 2022

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The EGFR is a protein that belongs to the ErbB family of tyrosine kinase receptors. The EGFR is often overexpressed in human carcinomas. Amplification of the EGFR gene and mutations in the EGFR tyrosine kinase domain occur in patients with cancer. In cervical cancer, the expression level of the EGFR protein appears to directly associate with human papillomavirus infection. Our previous research demonstrated that in the cervical cancer cell lines, CALO and INBL, the EGFR is non-phosphorylated. The aim of the current study was to analyze the catalytic activity of the isolated EGFR and the presence of mutations in the control region αC. Catalytic activity was assessed by a universal in vitro kinase assay using polyGluTyr as a substrate, and the proteins were visualized by western blotting. For mutation analysis, DNA from CALO and INBL cell lines was isolated, and PCR was used to amplify the exons corresponding to the helix αC in the EGFR. The PCR products were visualized by agarose gel electrophoresis. The bands were isolated using a Zymoclean Gel DNA Recovery kit and directly sequenced. The EGFR, which was isolated and analyzed using the in vitro kinase assay, had catalytic activity. The receptor contained some mutations in the helix αC of the catalytic domain in both cell lines. The observed changes in the amino acid sequence may induce a different spatial arrangement and, therefore, a different conformation, which may confer different activities to this receptor. Thus, it was concluded that non-phosphorylated EGFR has catalytic activity, and it bears some amino acid changes in the helix αC of the catalytic domain in the CALO and INBL cells. These results suggest that the EGFR may function as an activator of other ErbB family receptors in these cervical cancer cells.

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The Tyrphostin B42 Inhibits Cell Proliferation and HER-2 Autophosphorylation in Cervical Carcinoma Cell Lines

Cited by 6 publications

References 29 publications

Tyrphostin B42 attenuates trichostatin A-mediated resistance in pancreatic cancer cells by antagonizing IL-6/JAK2/STAT3 signaling

Tyrphostin B42 attenuates trichostatin A-mediated resistance in pancreatic cancer cells by antagonizing IL-6/JAK2/STAT3 signaling

Pleiotropic Effects of IL-2 on Cancer: Its Role in Cervical Cancer

Mutations in the helix αC of the catalytic domain from the EGFR affect its activity in cervical cancer cell lines

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