Second Low-oxygen Pathway Hints At Cancer, Cardiovascular Disease Physiology

Oxygen sensing, the ability of a cell to gauge the oxygen concentrations in its environment and to protect itself through internal regulation, is a fundamental process in most species of animals that depend entirely on oxygen to maintain cellular function. There are multiple, oxygen-dependent pathways in the cell that are regulated by changes in oxygen levels.

By starving human cells of oxygen, Celeste Simon, PhD, Professor of Cell and Developmental Biology at Penn and a Howard Hughes Medical Institute (HHMI) Investigator, and colleagues discovered an oxygen-sensitive cellular pathway that leads to a decrease in protein synthesis. This finding is the second hypoxic cellular pathway to be identified by this research team. Simon, who is also a member of Penn's Abramson Cancer Center, and colleagues report their most recent findings in the February issue of Molecular Cell.

In order to promote cellular adaptations to hypoxia, the cell must first recognize the presence of a low-oxygen environment. Previous genetic studies from Simon's laboratory helped to establish that the mitochondria–the energy center of the cell–play a major role in oxygen sensing. Like an alarm, mitochondria alert the cells when oxygen levels fall too low, resulting in hypoxic cells activating a protein called hypoxia-inducible factor (HIF). HIF, in turn, signals for physiological changes in nearby tissue that serve to protect oxygen-deprived cells. These changes include an increase in the number of red blood cells and blood vessels, the dilation of vessels, and changes in cell motility.

"These physiological changes make biological sense," explains Simon. "The changes allow the affected cell, or tissue, to withstand the stress of low oxygen. Changes in the blood cells and vasculature enhance the ability of the blood stream to carry oxygen to the effected regions."

In their most recent studies, Simon's group revealed the ability of cells to adapt to low-oxygen concentrations through a second molecular pathway. In order to protect itself during hypoxic conditions, a cell will conserve energy by greatly reducing protein synthesis. By exposing human cells to low-oxygen conditions, the researchers observed the inactivation of mTOR, a central regulator of global protein synthesis. Further genetic testing revealed that the mTOR pathway operates independent of the HIF pathway.

Though paradoxical, Simon's findings suggest that the HIF pathway leads to the activation and translation of nearly 200 target genes essential to the cell's protective physiological changes, while the second and most recently discovered pathway–the mTOR pathway–inhibits protein synthesis. "The cell needs to take what energy it has to redirect to the molecular response that results in the necessary physiological changes," Simon suggests.

"There is something about the messenger RNAs present in the HIF pathway that allows them to escape inhibition of global protein synthesis," Simon notes. She believes that the directions for these mRNAs to move forward and make protein, while many are left behind, lies in the genetic makeup of mRNA. Her lab is currently working to identify these molecular directions.

Although hypoxic conditions exist throughout early embryonic development, the presence of hypoxic environments in adult tissue is often a response to disease. As Simon explains, "A lot of the major Western world scourges involve a decrease in oxygen availability that falls below the threshold that cells need to remain healthy and carry out their functions." Hypoxia is a prominent component of solid tumors, myocardial infarctions, stroke, diabetic retinopathy, inflammation, and atherosclerosis.

In addition to hypoxia, solid cancer tumors are comprised of abnormal cells and convoluted blood vessels, which allow the tumors to resist chemotherapy and radiation treatments. New treatments for cancer are now aiming to turn off HIF and mTOR activity, halting the ability of the cell to signal its low-oxygen alert system and undergo protein synthesis.

"If we are able to create a treatment for tumors by inactivating the factor that is promoting cell survival and tumor cell motility – a key regulator of tumor metastasis – we may have another option to treat solid tumors," notes Simon.

Study co-authors are Liping Liu, Timothy P. Cash, Russell G. Jones, Brian Keith and Craig B. Thompson, all from the Abramson Family Cancer Research Institute (AFCRI). The research was funded by the National Institutes of Health, HHMI, and AFCRI.