Recent research sheds light on how changes in the chemical structure of a protein called Interleukin-6 affect lung cancer’s growth and response to treatment. Scientists from National Cheng Kung University and other leading institutions discovered that an abnormal chemical modification, called defective N-glycosylation, in Interleukin-6 causes cancer cells to spread more easily and resist certain treatments. N-glycosylation refers to a process where sugar molecules attach to specific sites on proteins, affecting how they function. These findings, published in the journal Nature Communications, highlight a crucial factor in how lung cancer evolves and becomes harder to treat.
Researchers led by Professor Wu-Chou Su and Chun-Hua Hung studied how chemical changes in Interleukin-6 influence pathways that control cancer cell behavior. “The way Interleukin-6 is modified chemically can help us monitor how lung cancer progresses and becomes resistant to drugs,” said Professor Su. The study revealed that when a sugar molecule is added to Interleukin-6 at a specific site, it activates a pathway called Janus Kinase-Signal Transducer and Activator of Transcription 3, which keeps the cancer in check. This pathway is a series of chemical reactions inside cells that help regulate growth and survival. However, when this chemical change does not occur, Interleukin-6 triggers a different pathway, making the cancer more aggressive.
Cancer cells that lack this modification in Interleukin-6 showed stronger traits for spreading to other parts of the body. These cells also resisted targeted therapies that usually block cancer growth, such as tyrosine kinase inhibitors, which are drugs designed to interrupt cancer’s growth signals. Analysis of patient samples confirmed that these resistant cancers had higher levels of abnormally modified Interleukin-6, strengthening the link between this defect and drug resistance.
Remarkably, the study found that this chemically defective Interleukin-6 changes how cancer cells communicate internally. While the modified version of the protein activates signals that slow cancer growth, the defective form sends signals that increase the cancer’s ability to move and survive. It activates proteins known for making cancer stem-like, which means they gain the ability to grow and spread indefinitely like stem cells. “This switch in signaling highlights a new way cancer avoids being treated successfully,” said Hung.
These findings have practical implications. Testing for the specific types of Interleukin-6 in patients could help predict whether their cancer will resist treatment. Additionally, new therapies that block the harmful effects of defective Interleukin-6 or restore its normal chemical state could provide better outcomes for lung cancer patients.
Breaking new ground, this research shows how small chemical differences in a single protein can drastically alter how a cancer behaves. It opens the door to innovative treatments that target these chemical changes, offering hope for tackling drug-resistant lung cancer.
Journal Reference
Chun-Hua Hung, Shang-Yin Wu, Cheng-I Daniel Yao, et al., “Defective N-glycosylation of IL6 induces metastasis and tyrosine kinase inhibitor resistance in lung cancer.” Nature Communications, 2024. DOI: https://doi.org/10.1038/s41467-024-51831-7
About the Authors
Professor Wu-Chou Su is a distinguished expert in medical oncology and currently serves as Professor Emeritus in the Department of Oncology at National Cheng Kung University (NCKU) in Tainan, Taiwan. He previously held key leadership roles at NCKU, including Director of the Department of Oncology and the Center of Applied Nanomedicine. In addition, he has overseen the Clinical Trial Center, Cancer Center, and the Department of Internal Medicine at National Cheng Kung University Hospital.
Professor Su’s research interests focus on early-phase clinical trials, the pathogenesis and treatment of lung cancer, and the role of the IL-6/JAK/STAT3 signaling pathway in lung cancer progression. He is also deeply involved in the development of nanodiagnostics and nanodrugs as innovative anti-cancer strategies. Throughout his career, Professor Su has published extensively and led numerous clinical trials in the fields of lung cancer and nanomedicine.
Dr. Chun-Hua Hung recieved her Ph.D. from the Institute of Basic Medical Sciences at National Cheng Kung University (NCKU) at Tainan, Taiwan. She is currently a postdoctoral research fellow at NCKU. Her research interests lies in tumor biology, focusing on the role of protein glycosylation in cancer metastasis, drug resistance, immune modulation, and spatial cancer biology.
Chun-Hung Lin received PhD in Chemistry in 1995 from Scripps Research Institute and spent two years for postdoctoral training at Harvard Medical School. He then started his independent career at Academia Sinica, Taiwan. He received several awards and honors, including Young Affiliate of TWAS (The Academy of Sciences for the Developing World), and Outstanding Research Award from National Science and Technology Council in Taiwan. His research interest is to study carbohydrate-based recognitions in cancers and infectious diseases (including host-microbe interplay).
Dr. Cheng-I Daniel Yao received his Ph.D. in Plant Biology from the College of Liberal Arts and Sciences at Arizona State University. Over the past ten years at Academia Sinica, he has worked in the field of glycosciences, focusing on glycan purification and analysis, as well as lectin-glycan interactions. His research expertise lies in structural analysis in bacterial glycans and glycolipids correlating to immune responses in host gut immunity.
