Aberrant FGFR tyrosine kinase signaling enhances the warburg effect by reprogramming LDH Isoform expression and activity in prostate cancer

Junchen Liu, Guo Chen, Zezhen Liu, Shaoyou Liu, Zhiduan Cai, Pan You, Yuepeng Ke, Li Lai, Yun Huang, Hongchang Gao, Liangcai Zhao, Helene Pelicano, Peng Huang, Wallace L. McKeehan, Chin Lee Wu, Cong Wang, Weide Zhong, Fen Wang

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

The acquisition of ectopic fibroblast growth factor receptor 1 (FGFR1) expression is well documented in prostate cancer progression. How it contributes to prostate cancer progression is not fully understood, although it is known to confer a growth advantage and promote cell survival. Here, we report that FGFR1 tyrosine kinase reprograms the energy metabolism of prostate cancer cells by regulating the expression of lactate dehydrogenase (LDH) isozymes. FGFR1 increased LDHA stability through tyrosine phosphorylation and reduced LDHB expression by promoting its promoter methylation, thereby shifting cell metabolism from oxidative phosphorylation to aerobic glycolysis. LDHA depletion compromised, whereas LDHB depletion enhanced the tumorigenicity of prostate cancer cells. Furthermore, FGFR1 overexpression and aberrant LDH isozyme expression were associated with short overall survival and biochemical recurrence times in patients with prostate cancer. Our results indicate that ectopic FGFR1 expression reprograms the energy metabolism of prostate cancer cells, representing a hallmark change in prostate cancer progression. Significance: FGF signaling drives the Warburg effect through differential regulation of LDHA and LDHB, thereby promoting the progression of prostate cancer. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/16/4459/F1.large.jpg.

Original languageEnglish (US)
Pages (from-to)4459-4470
Number of pages12
JournalCancer research
Volume78
Issue number16
DOIs
StatePublished - Aug 15 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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