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. 2017 Nov 26;18(11):2977-2983.
doi: 10.22034/APJCP.2017.18.11.2977.

Effect of Targeted Therapy With Pazopanib on Expression Levels of Transcription, Growth Factors and Components of AKT/m-TOR Signaling Pathway in Patients With Renal Cell Carcinoma

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Free PMC article

Effect of Targeted Therapy With Pazopanib on Expression Levels of Transcription, Growth Factors and Components of AKT/m-TOR Signaling Pathway in Patients With Renal Cell Carcinoma

Liudmila V Spirina et al. Asian Pac J Cancer Prev. .
Free PMC article

Abstract

Background: The effect of the targeted therapy on cancer molecular markers remains currently unknown. The aim of the study was to investigate the expression and content of transcription, growth factors and components of the AKT/m-TOR signaling pathway in kidney cancer patients before and after targeted therapy with pazopanib. Methods: A total of 157 patients with renal cell carcinoma were enrolled into the study. The level of mRNA expression was investigated by real-time PCR, and the contents of transcription and growth factors, as well as the levels of AKT/m- TOR signaling pathway components were determined by ELISA and Western blotting. Results: Targeted therapy with pazopanib resulted in a 3.1-fold decrease in HIF-2α expression that was accompanied by a reduction in the levels of NF-κB p65 and p50, HIF-1α and CAIX. The levels of GSK-3ß and AKT mRNA were increased; however, the levels of corresponding proteins remained low. The targeted therapy with pazopanib did not influence the level of PTEN phosphatase. A 1.9-fold increase in the level of p70 S6 (S371) was observed after therapy. Conclusion: The efficacy of tyrosine kinase inhibitors is associated with the changes in the angiogenic factors. Molecular characteristics of cancer could determine markers of disease progression as well as potential targets for anticancer therapies

Keywords: kidney cancer; metastasis; pazopanib.

Figures

Figure 1
Figure 1
Expression of NF-kB p50, NF-kB p65, HIF-2, HIF-1α (a), VEGF, peцeптopa VEGFR2 и, CAIX (b) in cancer tissues, M – is a stage of cancer: 0 – non-metastatic cancer, 1 – metastatic cancer. In patients with metastatic RCC, a 8.5-, 19.8- and 13.4-fold increase was observed in the VEGF, CAIX and VEGFR2 expressions, respectively. The study showed that the level of HIF-1α transcription factor was 1.5 times higher in patients with disseminated RCC compared to that observed in patients with localized RCC.
Figure 2
Figure 2
Levels of NF-kB p50, NF-kB p65, HIF-1α (a); HIF-2, CAIX b); VEGF. VEGFR2 (c) in Cancer Tissues, M – is a Stage of Cancer: 0 – non-metastatic cancer, 1 – metastatic cancer. The levels of VEGF and VEGFR2 receptor were respectively 2.3 and 1.78 times higher in metastatic compared to non-metastatic cancer tissues. On the contrary, the CAIX level was 1.5 times lower in patients with metastatic disease compared to those who had localized cancer.
Figure 3
Figure 3
Immunoblots of AKT/m-TOR Components in Kidney Cancer Tissues. a – AKT, phospho-PDK1, phospho-c-Raf, phospho-GSK-3beta and phospho-PTEN level in non transformed (1) and cancer (2) tissues; b – m-TOR, phospho-m-TOR, 70S 6 kinase and 4E-BP1 levels in non transformed (1) and cancer (2) tissues. Note: The results were standardized using the beta-actin expression in a sample and were expressed in percentages to the protein content in non-transformed tissues. The level of protein in normal non-altered tissue was indicated as 100%. It is found the activation of AKT/m-TOR signaling pathway in kidney cancers by increase of AKT, its phosphorylated form, proteinkinase m-TOR, glycogen regulator GSK-3-ß and transcription inhibitor 4E-BP1.

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