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GDF15 knockdown and response to treatment with temozolomide and radiotherapy in glioblastoma cell lines

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Author(s):
Mirella Baroni
Total Authors: 1
Document type: Master's Dissertation
Press: Ribeirão Preto.
Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
Defense date:
Examining board members:
Carlos Alberto Scrideli; Carlos Gilberto Carlotti Junior; Suely Kazue Nagahashi Marie
Advisor: Carlos Alberto Scrideli
Abstract

Glioblastoma (GBM) is the most common and most malignant primary brain tumors in adults. Exhibits complex genetic changes that leads to malignant progression, and resistance to standard therapies. Among the genetic alterations, our group observed a high expression of GDF15 in primary GBM tumors. The GDF15 is a growth factor that under normal physiological conditions is weakly expressed but in case of inflammations and malignancies your expression is increased. The high level of GDF15 is associated with poor prognosis and radio and chemoresistance in many types of tumors. This project aimed to correlate the silencing of GDF15 with sensitivity to radiotherapy and TMZ in adult and child GBM cell lines. To analyze these correlations, was made the analysis of GDF15 expression in GBM cell lines by qRT-PCR. The two cell lines that expressed more were transduced by the technique of short hairpin RNA (shRNA), which promoted the knockdown of GDF15. After verifiy the inhibition of GDF15 gene and protein, were made independent treatments (radiotherapy and TMZ) followed by in vitro assays. Eight of nine GBM cells lines showed high expression of GDF15. The pediatric GBM cell line, KNS42 and adult GBM cell line, U343, had the higher expression of GDF15 compared with normal tissue. After silencing, KNS42 showed decreased clonogenic capacity compared with control, but there was no change at cell proliferation. The U343 was not affected by GDF15 inhibition. The silencing associated with TMZ only had effect in increasing proliferation of U343 with significant data after 72 hours of treatment. The KNS42 showed no change in sensitivity to TMZ after the GDF15 silencing. The silencing associated with radiotherapy had effect at U343, which showed a lower fraction of surviving colonies in the silenced cell line at the 4Gy dose, compared with the control cell line. The KNS42 showed no correlation between silencing and sensitivity to radiotherapy. These data show that silencing of GDF15 promoted different responses in U343 and KNS42 cell lines, which can be explained by different molecular characteristics of GBM pediatric and adult. (AU)

FAPESP's process: 12/11351-6 - Silencing of GDF15 gene and response to radiotherapy and Temozolomide treatment of glioblastoma multiforme cell lines
Grantee:Mirella Baroni Milan
Support type: Scholarships in Brazil - Master