A City of Hope researcher has figured out what kickstarts a critical chain reaction that tumor cells can use to protect themselves from cell-killing chemotherapy or radiation. This finding could lead to more effective cancer-fighting therapies.
Yuan Chen, Ph.D., professor in Beckman Research Institute’s Division of Immunology, defined the first step of how proteins become decorated with smaller proteins known as ubiquitin-like modifiers. She and colleagues reported their findings in the July issue of Molecular Cell.
Accessorizing proteins with small ubiquitin-like proteins is an important way to control various cellular activities, such as a protein’s lifespan or where it resides inside a cell.
Chen’s laboratory specifically focuses on a ubiquitin-like protein called SUMO (shorthand for small ubiquitin-related modifier).
Adding SUMO to specific targets — a process called sumoylation — helps cells fight off genetic damage done by radiation or chemicals, though scientists do not know exactly how that happens.
“SUMO is definitely critical for DNA repair,” explained Chen, a structural biologist. “That was demonstrated in several studies. If you suppressed sumoylation, you saw increased sensitivity to radiation and DNA-damaging chemotherapeutic drugs.”
This suggests a novel treatment strategy: If scientists could inhibit the sumoylation machinery in a cancer cell, that cell could become more vulnerable to radiation or chemotherapy.
Many chemotherapeutic drugs — as well as radiation — kill tumor cells by damaging a cell’s DNA. Unfortunately, tumor cells sometimes fight back by fixing that damage, presenting a major challenge to oncologists. “Mobilization of DNA repair is part of why tumor cells become resistant to radiation and chemotherapy,” Chen explained. If sumoylation is part of that response, blocking it could foil the counterattack, she added.
Chen is an expert in nuclear magnetic resonance, or NMR, which allows investigators to visualize the three-dimensional structure of proteins and DNA at atomic resolution. Chen used NMR to actually see the enzymes that kick off sumoylation.
Three of those enzymes — named E1, E2, and E3 — form a molecular bucket brigade that passes a SUMO molecule to a target protein. Chen imaged precisely how E1 nudges and then relays SUMO to E2. Similar interactions likely modify proteins by other ubiquitin-like factors.
Understanding how the SUMO hand-off occurs could suggest ways to block it.
“Knowing how an inhibitor binds could give you important information on how to design an effective drug,” says Chen, who is working to identify such a drug with David Horne, Ph.D., professor and associate chair of molecular medicine and director of City of Hope’s synthetic chemistry core facility.
Drugs that interfere with similar ubiquitin-type modifications are in clinical trials, and some have been approved for cancer treatment. “We feel that SUMO-related inhibitors have similar potential,” said Chen.
Contributors also included Jianghai Wang, Ph.D., Weidong Hu, Ph.D., and Brian Lee from the Division of Immunology, along with former research fellow Sheng Cai, Ph.D., and former City of Hope graduate student Jing Song, Ph.D.
The National Institutes of Health funded the research.