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Abstract
Cancer cachexia is a muscle-wasting syndrome that leads to a severely compromised quality of life and increased mortality. A strong association between cachexia and poor prognosis has been demonstrated in intractable cancers, including glioblastoma (GBM). In the present study, it was demonstrated that ionizing radiation (IR), the first-line treatment for GBM, causes cancer cachexia by increasing the exosomal release of plasminogen activator inhibitor-1 (PAI-1) from glioblastoma cells. Exosomal PAI-1 delivered to the skeletal muscle is directly penetrated in the muscles and phosphorylates STAT3 to intensify muscle atrophy by activating muscle RING-finger protein-1 (MuRF1) and muscle atrophy F-box (Atrogin1); furthermore, it hampers muscle protein synthesis by inhibiting mTOR signaling. Additionally, pharmacological inhibition of PAI-1 by TM5441 inhibited muscle atrophy and rescued muscle protein synthesis, thereby providing survival benefits in a GBM orthotopic xenograft mouse model. In summary, our data delineated the role of PAI-1 in the induction of GBM cachexia associated with radiotherapy-treated GBM. Our data also indicated that targeting PAI-1 could serve as an attractive strategy for the management of GBM following radiotherapy, which would lead to a considerable improvement in the quality of life of GBM patients undergoing radiotherapy.

Affiliations

Eunguk Shin 1, Hyunkoo Kang 1, Haksoo Lee 1, Sungmin Lee 1, Jaewan Jeon 2, Kimoon Seong 3, Hyesook Youn 4, Buhyun Youn 1 5
1Department of Integrated Biological Science, Pusan National University, Busan 46241, Korea.
2Department of Radiation Oncology, Haeundae Paik Hospital, Inje University College of Medicine, Busan 48108, Korea.
3Laboratory of Biological Dosimetry, National Radiation Emergency Medical Center (NREMC), Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul 01812, Korea.
4Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul 05006, Korea.
5Department of Biological Sciences, Pusan National University, Busan 46241, Korea.