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Antagonistic actions of FGF2 in tumor cells of mice: mitogenesis shooting and cell death

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Author(s):
Erico Tosoni Costa
Total Authors: 1
Document type: Doctoral Thesis
Press: São Paulo.
Institution: Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ)
Defense date:
Examining board members:
Hugo Aguirre Armelin; Roger Chammas; Alicia Juliana Kowaltowski; Robert Schumacher; Chao Yun Irene Yan
Advisor: Hugo Aguirre Armelin
Abstract

The purpose of this work is to study the role of FGF2 (fibroblast growth factor-2) in the cell cycle control of mammalian cells. Our model of study is the lineage Y1, derived from a murine adrenocortical functional tumor, which presents the proto-oncogene c-ki-ras amplified and, as a consequence, exhibits enhanced expression of the c-Ki-Ras protein in its active forms (c-Ki-Ras-GTP). Arrested Y1 cells in the G0/G1 interface of the cell cycle are promptly responsive to FGF2 treatments, responding with progression through G0/G1 → S, but surprisingly, under the same conditions, FGF2 elicits a strong death response in cultured or in vivo cells, blocking the progress in the cell cycle after S phase entry. Under low c-Ki-Ras-GTP conditions, Y1 cells respond to FGF2 with enhanced proliferation, showing that death induction is related to c-Ki-Ras-GTP levels. Moreover, the Y1 population is heterogeneous, with a majority of FGF2-sensitive cells, and a minority of cells that can be positively selected in the presence of FGF2. These FGF2-resistant cells exhibit a proliferative response to FGF2 and phenotypic traits close to those observed in normal cells, even though the mechanisms of resistance are independent of c-Ki-Ras-GTP decrease. Comparable to that, normal lineages 3T3 display a mitogenic response to FGF2 that is substituted by a death response after their transformation with the oncogene EJ-Ras. The collection of our results associated with a review in the bibliography lead us to suggest a new biological effect of FGF2: enhanced protection against tumors originated by oncogenes. (AU)