The traditional paradigm in cancer drug development is to target the aberrant protein or stretch of DNA that is wreaking havoc within the cell. Now, a team of University of California, Berkeley scientists is looking past the traditional molecules at an entirely new set of potential targets: RNA.
Specifically, the researchers focused on messenger RNA (mRNA), which is generated within the cell’s nucleus and shuttled to the cytoplasm to link up with the protein generation machinery that resides there.
In the past, many scientists believed that mRNA contained too few distinguishing features that would designate them as suitable drug targets. However, the UC Berkeley team discovered that a small subset of the total cellular mRNA carried a unique tag that binds to the eukaryotic initiation factor 3 (eIF3) protein, which regulates translation at the ribosome.
“We've discovered a new way that human cells control cancer gene expression, at the step where the genes are translated into proteins. This research puts on the radar that you could potentially target mRNA where these tags bind with eIF3,” said Jamie Cate, Ph.D., professor of molecular and cell biology at UC Berkeley and senior author on the study. “These are brand new targets for trying to come up with small molecules that might disrupt or stabilize these interactions in such a way that we could control how cells grow.”
The findings from this study were published recently online in Nature through an article entitled “eIF3 targets cell-proliferation messenger RNAs for translational activation or repression.”
Interestingly, Dr. Cate and his team found that the majority of the tagged mRNA molecules coded for proteins that were in some way linked to cancer development or progression—the expression of which are often tightly regulated in order to keep the cell proliferation pathways in check. To their surprise, Dr. Cate’s team observed that the tags were bifunctional, turning mRNA translation on for some and off for others.
“Our new results indicate that a number of key cancer-causing genes—genes that under normal circumstances keep cells under control—are held in check before the proteins are made,” explained Dr. Cate. “This new control step, which no one knew about before, could be a great target for new anticancer drugs.
“On the other hand,” Dr. Cate said, “the tags that turn on translation activate genes that cause cancer when too much of the protein is made. These could also be targeted by new anticancer drugs that block the activation step.”
Protein translation is a complex process that involves multiple proteins, with eIF3 being a major component of the initiation complex. Previous studies have shown eIF3’s role in regulating translation and stabilizing the overall structure of the protein making complex. Further research on eIF3 has shown a strong link between its overexpression and cancers of the esophagus, breast, and prostate.
“I think eIF3 is able to drive multiple functions because it consists of a large complex of proteins,” said Amy Lee, Ph.D., postdoctoral fellow in Dr. Cate's laboratory and first author on the current study. “This really highlights that it is a major regulator in translation rather than simply a scaffolding factor.”
Dr. Lee was also able to demonstrate in the laboratory that manipulating two of the eIF3 mRNA molecules discovered, both controlling cell growth processes, stopped cells from becoming invasive—a scenario often observed with aggressive metastatic tumors.
“We showed that we could put a damper on invasive growth by manipulating these interactions, so clearly this opens the door to another layer of possible anticancer therapeutics that could target these RNA-binding regions,” stated Dr. Cate.
