Role of the Tgf-beta/smad Pathway in Tumor Radioresistance to Boron Neutron Capture Therapy (Bnct) in a Human Colon Carcinoma Cell Line

Author:

Pastini Antonella1,Peralta Tomas1,Nievas Susana2,Carpano Marina1,Curotto Paula3,Pozzi Emiliano3,Thorp Silvia4,Rodriguez Carla1,Oglio Romina1,Perona Marina1,Thomasz Lisa1,Juvenal Guillermo1,Rossini Luciano1,Dagrosa Maria Alejandra1

Affiliation:

1. 1Department of Radiobiology. National Commission of Atomic Energy (CNEA).

2. 2 Department of BNCT Coordination, CNEA

3. 3 RA-3 Nuclear Reactor, CNEA.

4. 4 Department of Instrumentation and Control, CNEA.

Abstract

Abstract

BNCT is a radiotherapy for different tumors as colorectal carcinoma (CRC). Although clinical outcomes show advantages of BNCT, tumor recurrence remains a common challenge. Previously we have described the double strand DNA damage response (DDR) produced by BNCT. TGF beta/SMAD pathway has been involved in maintaining genomic integrity. The aim of these studies was to evaluate the activation of the TGF-beta/SMAD pathway, its interaction with the DDR pathway and the possible use of LY2109761 (Ly), a specific inhibitor of TGF beta receptor, as a radiosensitizer for BNCT. Six groups were performed in a human colon adenocarcinoma (HT29) cell line: NCT (neutrons), BNCT (boronophenylalanine plus neutrons), Control and the same three groups with the addition of Ly. The results showed an activation of the TFG beta/Smad cascade with an increase in the genomic expression of TGF beta, Smad7 and Atr (p<0.001) at 2 hours post neutron treatments compared to the Control. A significant decrease in the expression of Tgf-beta receptor type I, Smad7 and Atr for BNCT plus Ly was observed. Furthermore, it was demonstrated a decrease in tumor survival as a function of the total absorbed physical dose for all the treatments, being significantly higher in the groups treated with Ly. On the other hand, a lower number of Ki67+ cells with the addition of Ly was found. Conclusion: The activation of the TGF-beta/SMAD pathway and its interaction with the DNA repair via through ATR transductor was demonstrated. LY2109761 could act as a radiosensitizer for BNCT.

Publisher

Research Square Platform LLC

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