Lung cancer cells, SEM

Researchers from the University of Southern California have discovered how lung cancer cells under stress can change the role of a protein to promote growth of and metastasis of these cells. The protein, called CRP78, can play a similar role in cells under stress in other diseases as well including Alzheimer’s disease, diabetes, and viral infections, among others.

The findings, published in the Proceedings of the National Academy of Sciences, is the surprise culmination of 40 years of research since the protein was first cloned by senior author Amy Lee, PhD, of the Keck School of Medicine at USC.

Typically, GRP78 resides in a part of the cell called the endoplasmic reticulum. But when cells are under stress, the chaperone protein migrates to the cell’s nucleus, where it alters gene activities and changes the behavior of the cell, allowing the cancer cells to become more mobile and invasive.

“This was a very surprising finding because GRP78 is supposed to be a shepherd protein sitting in the endoplasmic reticulum,” says Lee. “Once it is in the nucleus, it acts like a thief that has gone into the command center of your home or safe and then reprograms all the genes.

The new discovery started as an incidental one when Ze Liu, PhD, a postdoctoral researcher in Lee’s lab and the study’s first author, was analyzing how GRP78 regulates a gene known as EGFR, long linked to cancer. He noticed something surprising: GRP78 controls the gene activity of EGFR, raising the intriguing possibility that GRP78 may have entered the nucleus and assumed a new role. But the chaperone protein was long thought to exist primarily in the endoplasmic reticulum of cells.

To confirm their hypothesis, the team studied GRP78 in the nucleus of lung cancer cells, as well as normal cells under stress. They then used several other techniques to identify the signal within GRP78 that enables it to enter the nucleus and confirm that when GRP78 is present in the nucleus, it stimulates EGFR gene activity.

“In this paper, we identified a stretch of about 15 amino acids called the nuclear localization signal that is critical,” Lee explains. “Without that piece in GRP78 it cannot go into the nucleus from the endoplasmic reticulum.”

Next, the researchers set out to learn more about what happens in a cell after GRP78 enters the nucleus. They found that GRP78 binds to ID2, another cellular protein. ID2 typically suppresses genes (including EGFR), many of which allow cells to migrate.

“When GRP78 grabs ID2 as a hostage it can no longer do its job to shut down genes,” adds Lee. “And then a whole new set of genes are turned on.” Following bioinformatic data analysis her team discovered that the genes that are mostly turned on involve cell shape, migration, motility, and invasion. “Without the important suppression, the cancer cells become more invasive.

“So, for 40 years we never thought this protein could go into the nucleus,” Lee explains.  “But we now see that it does, interacts with transcription nuclear proteins, and completely rewrites the program changing the behavior of the cell.” While the present study analyzed lung cancer cells, GRP78 plays a similar role in various types of cancers, including pancreatic, breast, and colon cancer.

The new findings point to several potential new approaches for cancer treatment, including down-regulating the activity GPR78 to suppress EGFR in lung cancer, or preventing it from binding to ID2.

GRP78 could also bind to other proteins in the nucleus critical for cancer, opening a new line of research in cancer biology. “We believe that once GPR78 gets to the nucleus, the ID2 protein may just be the first prime candidate protein it talks to,” says Lee. “There must be other proteins it could talk to that are very important as well.”

In addition, Lee says that GRP78 in the nucleus also turns off a group of genes that her team has yet to analyze. “These discoveries prompt us to revisit our understanding of GRP78 and represent new areas to target, including inhibiting the expression or activity of GRP78,”  says Lee. The team is currently studying small molecules that inhibit GRP78 to block its activity in the nucleus of cells.

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