FM19G11 A new modulator of hif that links mTOR activation with the DNA damage checkpoint pathways
Por:
F. RODRIGUEZ-JIMENEZ, V. MORENO-MANZANO, P. MATEOS-GREGORIO, I. ROYO, S. ERCEG, J. MURGUIA and J. SANCHEZ-PUELLES
Publicada:
15 jul 2010
Resumen:
The network consisting of mTOR and p53 pathways is crucial to understanding a wide variety of physiological and pathological events, including cancer and aging. In addition, the HIF1 alpha protein, a downstream target of mTOR, is a hallmark of different tumor types and was the desired strategy of many drug discovery efforts. Here we present the novel chemical entity FM19G11, a new modulator of HIF1 alpha expression, which was used as a molecular tool to dissect and further characterize the cross-talk between these signaling cascades in human colon carcinoma cell lines. To our knowledge, FM19G11 is the first drug that triggers a DNA damage response (DDR) associated with G(1)/S-phase arrest in a p53-dependent manner, due to rapid hyper-activation of the growth signaling pathway through mTOR. Assessment of colonies demonstrated that FM19G11 decreases the clonogenicity of HT29, HCT116/p53(+/+) and HCT116/p53(-/-) cells. Moreover, FM19G11 causes significant lower colony growth in soft agar of p53-proficient human colon cancer cells. Consequently, p53 sensitizes human colon cancer cells to FM19G11 by significant reduction of their viability, lessening their colony formation capability and shrinking their anchorage-independent growth. Cell signaling studies served to assign a new mode of action to FM19G11, whose tumor-suppressant activity compromises the survival of functional p53 malignant cells.
Filiaciones:
:
Ctr Invest Principe Felipe, Cellular Reprogramming Lab, Valencia, Spain
:
Ctr Invest Principe Felipe, Cellular Reprogramming Lab, Valencia, Spain
P. MATEOS-GREGORIO:
Ctr Invest Principe Felipe, Cellular Reprogramming Lab, Valencia, Spain
I. ROYO:
Ctr Invest Biol, E-28006 Madrid, Spain
:
Ctr Invest Principe Felipe, Cellular Reprogramming Lab, Valencia, Spain
J. MURGUIA:
Univ Politecn Valencia, E-46071 Valencia, Spain
J. SANCHEZ-PUELLES:
Ctr Invest Biol, E-28006 Madrid, Spain
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