FM19G11: A new modulator of HIF that links mTOR activation with the DNA damage checkpoint pathways

Abstract

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 HIF1α 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 HIF1a 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 G1/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.