A surprising discovery from USC reveals important details about how cancer cells metastasize and suggests new treatment approaches to stop their spread.
The research centers on a cellular chaperone protein known as GRP78, which helps regulate the folding of other proteins inside cells. Amy S., professor of biochemistry and molecular medicine at USC’s Keck School of Medicine. Previous studies from the same team led by Lee showed that GRP78 is hijacked when cells are under stress (due to COVID-19 or cancer), allowing viral invaders to grow and heal.
Lee and her colleagues have now made an unexpected discovery that could enable scientists to protect cells from hostile takeover. Normally, GRP78 resides in a part of the cell called the endoplasmic reticulum. But when cells are stressed, the chaperone protein migrates into the cell’s nucleus, where it alters gene activity, altering cell behavior and allowing cancer cells to become more mobile and aggressive.
“It was quite surprising to see GRP78 in the nucleus regulating gene expression,” said Lee, the study’s senior author and the Judy and Larry Freeman Chair in Basic Science Research at the USC Norris Comprehensive Cancer Center. “When it comes to the underlying mechanisms of cancer cells, this is a novel approach that, to my knowledge, has not been observed before.”
Findings, just published Proceedings of the National Academy of Sciences, Cell biology could represent a paradigm shift, and could have implications for cancer treatment research, Lee said.
An unexpected discovery
The new invention started as an accident. Ze Liu, Ph.D., a postdoctoral researcher in Lee’s lab and first author of the study, was analyzing how GRP78 regulates a gene known as EGFR, which has long been associated with cancer. He noticed something surprising: GRP78 regulates the gene activity of EGFR, raising the intriguing possibility that GRP78 might enter the nucleus and take on a new role. But chaperone proteins were long thought to exist primarily in the endoplasmic reticulum of cells.
To confirm their hypothesis, Liu, Lee and their colleagues used confocal microscopy, which provides high-resolution 2D and 3D imaging and an advanced technology for capturing images of live cells, to directly observe GRP78 in the nucleus of lung cancer cells and normal cells under stress.
They then used several techniques, including biochemical analysis and mRNA “knock-down” of GRP78. These techniques allowed them to identify the signal within GRP78 that enables it to enter the nucleus, and confirm that when GRP78 is in the nucleus, it stimulates EGFR gene activity.
Next, the researchers set out to learn more about what happens in a cell after GRP78 enters the nucleus. Using a sophisticated form of RNA sequencing, they compared lung cancer cells engineered to overexpress GRP78 in the nucleus with cells without GRP78 in the nucleus to learn which genes were affected.
“To our surprise, we found that the key genes regulated by GRP78 in the nucleus were mainly related to cell migration and invasion,” Lee said.
The team found that GRP78 binds to another cellular protein, ID2. ID2 normally represses genes (including EGFR), many of which allow cells to migrate. But when bound to GRP78, ID2 can’t do its job. Without that suppression, cancer cells become more aggressive.
Broad implications for cancer and cell biology
The new findings point to several new approaches to cancer treatment, including reducing GPR78 activity to suppress EGFR in lung cancer, or blocking it from binding to ID2. GRP78 can bind to other proteins in the nucleus that are critical for cancer, opening a new avenue of research in cancer biology. When the present study analyzed lung cancer cells, GRP78 plays a similar role in different types of cancer, including pancreatic, breast, and colon cancers.
The discovery that GRP78, a major endoplasmic reticulum protein, can translocate to the nucleus and assume new functions will have broad implications throughout the field of cell biology. Other proteins that normally reside in one part of the cell can, under stress or other triggers, migrate to another part of the cell and change cell behavior in many ways, Lee said.
This is a new concept, she said. “The protein itself is the soldier doing the work, but now we’re thinking it’s not just about the soldier, but where the soldier is deployed.”
Lee and his team are also studying drugs that can block the expression or function of GRP78. A follow-up study by them suggests that small molecules that inhibit GRP78 YUM70It may even inhibit GRP78 activity in the nucleus of cells.
Liu, Ze et al, ER chaperone GRP78/BiP translocates to the nucleus under stress and acts as a transcriptional regulator, Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2303448120