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Cancer Res., Jul 29 2024, | https://doi.org/10.1158/0008-5472.CAN-23-3933 Targeting YAP Activity and Glutamine Metabolism Cooperatively Suppresses Tumor Progression by Preventing Extracellular Matrix Accumulation

Mihyang Park^1,2, Jonghwa Jin¹, Da Young An³, Dong-Ho Kim³, Jaebon Lee⁴, Jae Won Yun⁴, Ilseon Hwang⁵, Jae Seok Park⁶, Mi Kyung Kim⁶, You Mie Lee^7,8, Jun-Kyu Byun^8**, Yeon-Kyung Choi^2,9**, Keun-Gyu Park^1,2,3**

¹Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, South Korea

²Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41566, South Korea

³Department of Biomedical Science, Kyungpook National University, Daegu 41566, South Korea

⁴Veterans Medical Research Institute, Veterans Health Service Medical Center, Seoul 05368, South Korea.

⁵Department of Pathology, Keimyung University School of Medicine, Daegu 41931, South Korea

⁶Department of Internal Medicine, Keimyung University School of Medicine, Daegu 41931, South Korea

⁷College of Pharmacy, Vessel-Organ Interaction Research Center (VOICE, MRC), Kyungpook National University, Daegu 41566, Republic of Korea

⁸Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 41566, South Korea.

⁹Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu 41404, South Korea

^**Correspondence: Keun-Gyu Park, MD, PhD, Yeon-Kyung Choi, MD, PhD, Jun-Kyu Byun, DVM, PhD

Abstract

Cancer cells use multiple mechanisms to evade the effects of glutamine metabolism inhibitors. The pathways that govern responses to alterations in glutamine availability within the tumor may represent therapeutic targets for combinatorial strategies with these inhibitors. Here, we showed that targeting glutamine utilization stimulated Yes-associated protein (YAP) signaling in cancer cells by reducing cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)-dependent phosphorylation of large tumor suppressor (LATS). Elevated YAP activation induced extracellular matrix (ECM) deposition by increasing secretion of connective tissue growth factor (CTGF) that promoted production of fibronectin and collagen by surrounding fibroblasts. Consequently, inhibiting YAP synergized with inhibition of glutamine utilization to effectively suppress tumor growth in vivo, along with a concurrent decrease in ECM deposition. Blocking ECM remodeling also augmented the tumor suppressive effects of the glutamine utilization inhibitor. Collectively, these data reveal mechanisms by which targeting glutamine utilization increases ECM accumulation and identify potential strategies to reduce ECM levels and increase the efficacy of glutamine metabolism inhibitors.

논문정보

형식Research article
게재일2024년 07월 (BRIC 등록일 2024-07-30)
연구진국내 연구진
분야 의약학 > 응용의학

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