Upregulation of cytosolic phosphoenolpyruvate carboxykinase is a critical metabolic event in melanoma cells that repopulate tumors

Yong Li, Shunqun Luo, Ruihua Ma, Jing Liu, Pingwei Xu, Huafeng Zhang, Ke Tang, Jingwei Ma, Yi Zhang, Xiaoyu Liang, Yanling Sun, Tiantian Ji, Ning Wang, Bo Huang

Research output: Contribution to journalArticlepeer-review

Abstract

Although metabolic defects have been investigated extensively in differentiated tumor cells, much less attention has been directed to the metabolic properties of stem-like cells that repopulate tumors [tumor-repopulating cells (TRC)]. Here, we show that melanoma TRCs cultured in three-dimensional soft fibrin gels reprogram glucose metabolism by hijacking the cytosolic enzyme phosphoenolpyruvate carboxykinase (PCK1), a key player in gluconeogenesis. Surprisingly, upregulated PCK1 in TRCs did not mediate gluconeogenesis but promoted glucose side-branch metabolism, including in the serine and glycerol-3-phosphate pathways. Moreover, this retrograde glucose carbon flow strengthened rather than antagonized glycolysis and glucose consumption. Silencing PCK1 or inhibiting its enzymatic activity slowed the growth of TRCs in vitro and impeded tumorigenesis in vivo. Overall, our work unveiled metabolic features of TRCs in melanoma that have implications for targeting a unique aspect of this disease.

Original languageEnglish (US)
Pages (from-to)1191-1196
Number of pages6
JournalCancer Research
Volume75
Issue number7
DOIs
StatePublished - Apr 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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