Blocking a key cell pathway reduces muscle wasting in pancreatic cancer

Researchers at the University of Houston are pushing the boundaries of biomedical innovation with a discovery that could transform treatment for one of cancer's most devastating complications. 

In a new study published in EMBO Molecular Medicine, a team at the UH College of Pharmacy reports that blocking a particular cell pathway may offer a therapeutic strategy to counteract muscle wasting during pancreatic cancer-induced cachexia. Cancer cachexia is a debilitating syndrome characterized by the progressive loss of skeletal muscle mass and affects 60%–85% of patients with pancreatic cancer. 

Cellular pathways are groups of molecules that work like emergency alert systems for cells in trouble, receiving signals and determining responses. At UH, Ashok Kumar, Else and Philip Hargrove Endowed Professor of Drug Discovery and director of The Institute for Muscle Biology and Cachexia, has found that one pathway in particular is a culprit in causing muscles to weaken and shrink. 

"We show that the IRE1α/XBP1 pathway is a key contributor to muscle wasting," Kumar said. "Skeletal muscle-specific deletion of the XBP1 transcription factor significantly attenuates pancreatic tumor-induced muscle deterioration." The first author of the article is Aniket Joshi, a post-doctoral fellow in Kumar's lab. 

The IRE1α/XBP1 pathway operates in the endoplasmic reticulum, a cellular hub where proteins and fats are created. Muscle wasting in pancreatic cancer occurs primarily due to increased protein breakdown and reduced protein synthesis, leading to a net loss in the muscle protein content. 

"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," said Kumar. 

While the present study is focused on the role of IRE1α/XBP1 signaling in cachectic muscle, the pathways are also known to influence tumor growth, cancer progression and resistance to chemotherapeutic drugs. 

"The role of this pathway in the regulation of pancreatic cancer cell survival, especially in response to chemotherapeutic agents, needs further investigation," said Kumar.