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

Francisco Javier Rodríguez-Jiménez1, Victoria Moreno-Manzano, Pablo Mateos-Gregorio

  • 1Cellular Reprogramming Laboratory, Centro de Investigación Príncipe Felipe, Valencia, Spain. fjrodriguezjim@hotmail.com

Cell Cycle (Georgetown, Tex.)
|August 3, 2010
PubMed

Insights

We discovered FM19G11, a novel drug that halts colon cancer cell growth by triggering DNA damage and cell cycle arrest. This compound

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The mTOR and p53 pathways are critical in cancer and aging.
  • HIF1alpha, an mTOR target, is a key marker in tumors, driving drug discovery.
  • Understanding cross-talk between these pathways is vital for cancer research.

Purpose of the Study:

  • To introduce FM19G11, a novel HIF1alpha expression modulator.
  • To investigate the cross-talk between mTOR, p53, and HIF1alpha signaling in colon cancer.
  • To characterize FM19G11's mechanism of action and anti-cancer effects.

Main Methods:

  • Utilized human colon carcinoma cell lines (HT29, HCT116).
  • Assessed FM19G11's effect on clonogenicity and anchorage-independent growth.
  • Performed cell signaling studies to elucidate the drug's mode of action.

Main Results:

  • FM19G11 induces a p53-dependent DNA damage response and G1/S-phase arrest.
  • The drug hyper-activates mTOR signaling, leading to rapid growth pathway effects.
  • FM19G11 significantly reduces clonogenicity and soft agar growth, especially in p53-proficient cells.

Conclusions:

  • FM19G11 is the first drug to link DNA damage response with p53-dependent G1/S arrest via mTOR hyper-activation.
  • p53 status is crucial, as p53-proficient cells show increased sensitivity to FM19G11.
  • FM19G11 exhibits tumor-suppressant activity by compromising survival in malignant cells with functional p53.

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