Medical Professional Publications

Low Oxygen Partially Silences the Protein ATM, Allowing Many Treatment-Resistant Childhood Tumors to Grow

Many solid tumors are able to grow within an otherwise “toxic” environment because a protein that would normally stop cellular growth is partially silenced, suggests new research from Nationwide Children’s Hospital and St. Jude Children’s Research Hospital.

Solid tumors in children, including Wilms' tumor and neuroblastoma, are hypoxic, meaning that they do not receive an adequate amount of oxygen; yet, they survive and grow. Hypoxic tumor cells are usually resistant to radiation and chemotherapy, posing a unique challenge in treating patients with these tumors.

mTORC1 is a protein complex that is critical for cells to coordinate signals related to nutrition and intracellular stresses to ensure normal cell growth. “Hypoxia, which occurs early and in most solid tumors should suppress mTORC1 signaling,” said Peter J. Houghton, PhD, director of the Center for Childhood Cancer at The Research Institute at Nationwide Children’s Hospital and study author. “Yet, inappropriate control of mTORC1 activity is a hallmark of many benign and malignant human tumors.  This suggests that in order for these tumor cells to grow and spread, mTORC1 must somehow become dysregulated. However, it hasn’t been clear as to how hypoxia is linked to inappropriate mTORC signaling.”  

In a study appearing in Molecular Cell, Dr. Houghton and colleagues discovered that the stress sensor protein Ataxia Telangiectasia Mutated (ATM), which is important in DNA repair and programmed cell death, may serve as this possible link. When examining models of childhood solid tumors, the team found that these tumors have an abnormally low level of ATM compared to their tissue of origin and compared to leukemia models. Further investigation showed that ATM is the trigger necessary for appropriate mTORC1 regulation.  In hypoxic conditions, ATM is downregulated, ATM-deficient cells fail to regulate mTORC1 and the tumor cells continue to progress through their growth process.

“These data suggest that partial silencing of ATM is an early step in the childhood solid tumor development and progression and represents an important addition to the several other ways in which TORC1 activity can remain elevated in hypoxic tumors,” said Hakan Cam, PhD, principal investigator in the Center for Childhood Cancer at The Research Institute and study author. Being able to eliminate the silencing of ATM in solid tumors could potentially serve as a new treatment strategy that would arrest growth and induce tumor cell death for these difficult-to-treat childhood tumors.

Cam H, Easton JB, High A, Houghton PJ. mTORC1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α. Mol Cell. 2010 Nov 24;40(4):509-20.

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