Dual Role of Protein a Potential New Mechanism of Cancer Growth

The protein inositol-requiring enzyme 1 (IRE1) plays a dual role in cancer, in which it either promotes or inhibits tumor growth, according to recent findings.

IRE1 is regulated by the protein Ras, which plays a crucial role in cancer. Normally, Ras helps manage cell growth and division; however, when mutated it can cause different cancers.

In a study published in the Proceedings of the National Academy of Sciences, investigators used skin cells derived from mice and found oncogenic Ras causes buildup of unfolded proteins in the endoplasmic reticulum (ER). As a result, incorrectly folded proteins activate IRE1 while trying to reduce the unfolded stress response, according to the study.

“We still don’t know how Ras is causing the stress response, whether because the cells are more proliferative, or because of other unknown factors outside or inside the cell, but the end result seems to be increased unfolded proteins in the ER,” said investigator Adam Glick.

On one end, when IRE1 is activated, it reduces ER stress by degrading messenger RNAs, but it also causes expressions of proteins that fix unfolded proteins.

“While this action of IRE1 helps cells survive and may promote cancer development, one of the targets for this messenger RNA degradation pathway actually encodes an oncogenic protein called Id1,” Glick said. “It turns out that IRE1 has both pro-oncogenic and tumor-inhibiting capabilities that, by degrading this message, can counteract the tumor-promoting effects of oncogenic Ras. The end result is cells don’t continue to proliferate and undergo a process called senescence, or accelerated aging. Basically, they die.”

The findings are the first to link Ras and the dual role of IRE1 in cancer, noted first author Nicholas Blazanin.

“Discovering a potentially important new mechanism of cancer has been extremely gratifying,” Blazanin said.

Glick commented on the findings stating, “What this is really about is learning the basic biology of cancer to discover new ways to target the disease,” Glick said. “The more we know about the molecular circuitry—–and the mutations and genetics of cancer––the more we can design drugs that specifically target cancer cells without harming normal cells.”

The authors hope more research will provide a clearer picture of the mechanisms in other cancers.

“… by manipulating IRE1 we can potentially drive tumor cells to self-terminate,” Glick said. “We’re starting to test the hypotheses that we generated both on skin cancer and in lung cancer models because Ras is a really important driver of lung cancer in humans.”