December 11, 2023

In a discovery that has taken researchers by surprise, a protein known to play a key role in cancer growth has been observed for the first time to enter the nucleus of cells, flicking a switch and making cancers more mobile, aggressive and aggressive.

Inhibiting this mechanism could help curb a variety of cancers, including lung, kidney, stomach and prostate, making targeted therapies more effective.more than 90% of cancer deaths It is the result of cells spreading to other parts of the body, or metastasizing.

Stress is known to be a factor in cancer metastasis. Now, scientists have discovered that when cancer cells experience stress, the chaperone protein GRP78, also commonly known as BIP, located in the endoplasmic reticulum (ER), migrates to the nucleus to “hijack” gene activity. This essentially reprograms cellular behavior to make cancer harder to control.

“It was amazing to see GRP78 controlling gene expression in the nucleus,” said senior author Amy S. Lee, professor of biochemistry and molecular medicine at the Keck School of Medicine of USC. “When it comes to the fundamental mechanisms of cancer cells, as far as I know, this is something novel that no one has observed before.”

Human lung cancer cells engineered to overexpress GRP78 (TOP) in the nucleus. Cells lacking GRP78 in the nucleus (bottom). Green staining delineates the cytoskeletal protein F-actin, which controls cell shape and motility, and blue staining delineates the nucleus.
In the top row, human lung cancer cells engineered to overexpress GRP78 in the nucleus. In the bottom row, cells lack GRP78 in their nuclei.Green staining depicts the cytoskeletal protein F-actin, which controls cell shape and movement, and blue staining depicts the nucleus

Ze Liu, Amy Lee/Keck School of Medicine of USC

Earlier research has pointed out GRP78 plays an important role Cancer cells survive and proliferate, but the way it facilitates this process is not fully understood. The protein is also involved in the replication of the COVID-19 virus, increasing the likelihood of mutations leading to different, more vaccine-resistant strains.

chaperone protein GRP78 aids in the folding of other proteins within the cell, and GRP78 is thought to be present only in the endoplasmic reticulum.Using sophisticated RNA sequencing, scientists are able to see how it enters the ‘brains’ of cells to regulate genes under stress epidermal growth factor receptor And binds to the protein inhibitor ID2.

This “hostile takeover” results in ID2’s inability to lock down gene expression epidermal growth factor receptorleading to an increase in its activity, thereby making cancer cells more mobile and invasive.

“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.

Treatments that block GPR78 or prevent its binding to ID2 offer scientists a new avenue for research and development. While this study looked at lung cancer cells, GPR78 has similar functions in many other cancers. There may be other proteins that take on different roles, and when they are triggered and migrate, they change the behavior of the cell.

“This is a new concept,” Li said. “The protein itself is the soldier performing the mission, but now we think it’s not just about the soldier, but where the soldier is deployed.”

The team is currently searching for therapies that block the expression of chaperones, including known inducers of ER stress and GRP78 inhibitor YUM70.

The study was published in the journal Proceedings of the National Academy of Sciences.

source: Keck School of Medicine of USC