MCW Scientists Discover Targeting FBXO5 May Open the Door for New Colon Cancer Treatments

Intestinal ImagingDespite the scientific community’s ongoing efforts to understand how stress affects cells and contributes to colon cancer development, the exact mechanisms have remained elusive—until now. In a new global study, cancer researchers have unlocked new insights into a protein called FBXO5, revealing its crucial role in regulating cell survival during periods of stress in the endoplasmic reticulum (ER). MCW investigators say the study’s findings, recently published in Cell Death & Disease, mark a significant step forward in our understanding of colon cancer biology and open the door to potentially transformative treatments for the disease.

“We discovered that FBXO5 helps colon cancer cells survive under stress by degrading a protein called RNF183, which is involved in apoptosis (cell death). This discovery suggests that targeting the FBXO5 pathway could be a new strategy for colon cancer treatment,” said study co-author Wei Liu, PhD, Associate Professor of Pharmacology & Toxicology, and the Center’s Cancer Biology Research Program Co-Leader.

“Our groundbreaking work, supported by the Advancing a Healthier Wisconsin Endowment and facilitated by the invaluable resources of the Cancer Center, paves the way for innovative cancer treatment strategies. This collaboration displays our commitment to leveraging scientific research for the advancement of public health and highlights the crucial role of institutional support in propelling medical breakthroughs,” said Dr. Liu.

ER stress triggers a series of cellular responses that, if prolonged, can lead to cell death by activating specific signaling pathways that promote the breakdown of cell components, explained Dr. Liu. Using various molecular biology techniques and resources, including the Protein Production Facility located in the Cancer Center Structural Biology Shared Resource (SBSR), investigators discovered that lower levels of FBXO5 increase cell death in colon cancer cells under stress, suggesting that the protein helps these cells survive by preventing the activation of death pathways.

Colon cancer is one of the most commonly diagnosed cancers in the United States and is expected to account for nearly 107,000 new diagnoses in 2024. While rates of colon cancer have dropped steadily in older adults in the last few decades—mainly because more people are getting screened and changing their lifestyle-related risk factors—the rates have increased by 1% to 2% per year in adults younger than 55 since the mid-1990s. This alarming trend underscores the urgency for cancer scientists to identify new, effective treatment strategies for patients across populations.

“This research is the first to provide evidence that FBX05-targeted therapies may help combat the mechanisms driving colon cancer growth and survival. Our future work will explore how to effectively target the FBXO5-RNF183 pathway in cancer cells, potentially leading to the development of novel therapeutic strategies that can improve outcomes for people of all ages and backgrounds,” said Dr. Liu.

Read the full study in Cell Death & Disease.