FM19G11: A new modulator of HIF that links mTOR activation with the DNA damage checkpoint pathways.
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 HIF1alpha 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 HIF1alpha 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.
Rodríguez-Jiménez
Francisco Javier
FJ
Cellular Reprogramming Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain. fjrodriguezjim@hotmail.com
Moreno-Manzano
Victoria
V
Mateos-Gregorio
Pablo
P
Royo
Inmaculada
I
Erceg
Slaven
S
Murguia
José Ramón
JR
Sánchez-Puelles
Jose María
JM
D064007:Ataxia Telangiectasia Mutated Proteins; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D016193:G1 Phase; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007700:Kinetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016196:S Phase; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D001549:Benzamides; D001565:Benzoates; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C555528:FM19G11; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases