SPARC inhibits metabolic plasticity in ovarian cancer

Christine Naczki, Bincy John, Chirayu Patel, Ashlyn Lafferty, Alia Ghoneum, Hesham Afify, Michael A White, Amanda Davis, Guangxu Jin, Steven Kridel, Neveen Said

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

The tropism of ovarian cancer (OvCa) to the peritoneal cavity is implicated in widespread dissemination, suboptimal surgery, and poor prognosis. This tropism is influenced by stromal factors that are not only critical for the oncogenic and metastatic cascades, but also in the modulation of cancer cell metabolic plasticity to fulfill their high energy demands. In this respect, we investigated the role of Secreted Protein Acidic and Rich in Cysteine (SPARC) in metabolic plasticity of OvCa. We used a syngeneic model of OvCa in Sparc-deficient and proficient mice to gain comprehensive insight into the paracrine effect of stromal-SPARC in metabolic programming of OvCa in the peritoneal milieu. Metabolomic and transcriptomic profiling of micro-dissected syngeneic peritoneal tumors revealed that the absence of stromal-Sparc led to significant upregulation of the enzymes involved in glycolysis, TCA cycle, and mitochondrial electron transport chain (ETC), and their metabolic intermediates. Absence of stromal-Sparc increased reactive oxygen species and perturbed redox homeostasis. Recombinant SPARC exerted a dose-dependent inhibitory effect on glycolysis, mitochondrial respiration, ATP production and ROS generation. Comparative analysis with human tumors revealed that SPARC-regulated ETC-signature inversely correlated with SPARC transcripts. Targeting mitochondrial ETC by phenformin treatment of tumor-bearing Sparc-deficient and proficient mice mitigated the effect of SPARC-deficiency and significantly reduced tumor burden, ROS, and oxidative tissue damage in syngeneic tumors. In summary, our findings provide novel insights into the role of SPARC in regulating metabolic plasticity and bioenergetics in OvCa, and shines light on its potential therapeutic efficacy.

Original languageEnglish (US)
Article number385
JournalCancers
Volume10
Issue number10
DOIs
StatePublished - Oct 16 2018
Externally publishedYes

Keywords

  • Glycolysis
  • Metabolic plasticity
  • Ovarian cancer
  • OXPHOS
  • Peritoneal metastasis
  • Redox homeostasis
  • SPARC
  • Syngeneic model

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Naczki, C., John, B., Patel, C., Lafferty, A., Ghoneum, A., Afify, H., White, M. A., Davis, A., Jin, G., Kridel, S., & Said, N. (2018). SPARC inhibits metabolic plasticity in ovarian cancer. Cancers, 10(10), [385]. https://doi.org/10.3390/cancers10100385