Yap-Myc signaling induces pancreatic stellate cell activation through regulating glutaminolysis

• Published in: Experimental cell research 2022-02, Vol.411 (1), p.113000-113000, Article 113000
• Main Authors: Zhang, Dong, Zhao, Lin, Luo, Minna, Lei, Jianjun, Shao, Shan
• Format: Article
• Language: English
• Subjects: Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Proliferation; Cell Transdifferentiation; Desmoplasia; Glutamine - metabolism; Glutaminolysis; Glycolysis; Humans; Pancreatic cancer; Pancreatic Stellate Cells - cytology; Pancreatic Stellate Cells - physiology; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Signal Transduction; Transcription Factors - genetics; Transcription Factors - metabolism; Yap-Myc signaling
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2021.113000

The accumulation of activated myofibroblastic pancreatic stellate cells (MF-PSCs) induces pancreatic cancer desmoplasia. These MF-PSCs are derived from quiescent pancreatic stellate cells (Q-PSCs). MF-PSCs in pancreatic cancer tend to glycolysis. However, increased glycolysis alone could not be sufficient for the increased metabolic demands of MF-PSCs. Yap and Myc signaling activation is involved in pancreatic cancer metabolism. Since elucidating the metabolic processes of MF-PSCs may be a promising strategy to suppress pancreatic cancer desmoplasia, we explored whether glutaminolysis meets the bioenergetic and biosynthetic demands of Q-PSCs converted into MF-PSCs and whether this is mediated by Yap signaling to Myc. In this study, we found that during the transdifferentiation of Q-PSCs into MF-PSCs, glutaminolysis regulatory genes were upregulated, and suppression of glutaminolysis inhibited transdifferentiation. Disrupting glutaminolysis in MF-PSCs inhibited cell growth, mitochondrial respiration, and fibrogenesis, while treatment of MF-PSCs with DKG (a glutaminolysis metabolite) reversed these activities. The expression of glutaminase (GLS1), a rate-limiting enzyme in glutaminolysis, was upregulated by Yap overexpression. Yap upregulates Myc to regulate the expression of GLS1 in MF-PSCs. Yap and Myc inhibitors disrupted glutaminolysis and inhibited myofibroblastic activities in PSCs. Thus, Yap-Myc signaling controls glutaminolysis to activate PSCs and might be a therapeutic target for pancreatic cancer desmoplasia.