Researchers at the University of Houston have identified a potential new approach to reduce muscle wasting in patients with pancreatic cancer. The findings, published in EMBO Molecular Medicine, focus on blocking a specific cellular pathway that appears to play a key role in the development of cachexia, a syndrome marked by significant loss of skeletal muscle mass.
Cachexia affects between 60% and 85% of people with pancreatic cancer. It leads to progressive muscle deterioration, which can significantly impact quality of life and overall outcomes for patients.
The research team, led by Ashok Kumar, Else and Philip Hargrove Endowed Professor of Drug Discovery and director of The Institute for Muscle Biology and Cachexia at the UH College of Pharmacy, studied how the IRE1α/XBP1 pathway contributes to this condition. According to Kumar, "We show that the IRE1α/XBP1 pathway is a key contributor to muscle wasting. Skeletal muscle-specific deletion of the XBP1 transcription factor significantly attenuates pancreatic tumor-induced muscle deterioration." Aniket Joshi, a post-doctoral fellow in Kumar's lab, was the first author on the study.
The IRE1α/XBP1 pathway functions within the endoplasmic reticulum—the part of the cell responsible for producing proteins and fats. In cases of pancreatic cancer-induced cachexia, increased protein breakdown and decreased protein synthesis result in overall muscle loss.
Kumar explained further: "Our results also show that the IRE1α/XBP1 axis regulates multiple mechanisms that have a causative role in skeletal muscle wasting. Future studies will determine whether similar mechanisms are involved in muscle wasting in other models of cancer cachexia and pancreatic cancer patients."
While this study centers on how IRE1α/XBP1 signaling impacts cachectic muscle tissue, these pathways may also influence tumor growth, disease progression, and resistance to chemotherapy drugs. "The role of this pathway in the regulation of pancreatic cancer cell survival, especially in response to chemotherapeutic agents, needs further investigation," Kumar said.
