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Statin-induced GGPP depletion blocks macropinocytosis and starves cells with oncogenic defects

Zhihua Jiao1, Huaqing Cai2, Yu Long1

  • 1Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.

Proceedings of the National Academy of Sciences of the United States of America
|February 14, 2020
PubMed

Insights

Pitavastatin kills cancer cells by blocking geranylgeranyl diphosphate (GGPP) production, which impairs macropinocytosis and leads to nutrient starvation. This links the mevalonate pathway to cancer cell nutrient uptake for therapeutic targeting.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Cancer Research

Background:

  • The mevalonate pathway and macropinocytosis are implicated in cancer development.
  • A direct link between these two processes in tumorigenesis has not been established.
  • Targeting cancer-specific vulnerabilities is crucial for effective therapeutic strategies.

Purpose of the Study:

  • To investigate the connection between the mevalonate pathway and macropinocytosis in cancer cells.
  • To identify compounds that selectively target cancer cells based on these pathways.
  • To elucidate the mechanism by which mevalonate pathway inhibition affects cancer cell viability.

Main Methods:

  • Utilized a compound library screen in *Dictyostelium discoideum* to identify selective cell-killing agents.
  • Tested the efficacy of identified compounds, such as pitavastatin, in human cancer cell lines and mouse tumor organoids.
  • Investigated the role of geranylgeranyl diphosphate (GGPP) in macropinocytosis and cell survival through genetic disruption.
  • Assessed nutrient uptake and cell death mechanisms following drug treatment.

Main Results:

  • Pitavastatin selectively killed cancer cells with oncogenic mutations (PTEN loss or K-Ras activation) by depleting GGPP.
  • GGPP is essential for pseudopod extension and macropinocytosis, processes vital for nutrient uptake.
  • Cancer cells rely on macropinocytosis for nutrient uptake, making them sensitive to drugs that disrupt this process.
  • Inhibition of macropinocytosis led to amino acid starvation and cell death in oncogenically altered cells.

Conclusions:

  • The mevalonate pathway is critical for cancer cell survival due to its role in supplying GGPP for macropinocytosis.
  • Cancer cells' increased reliance on macropinocytosis for nutrient uptake creates a therapeutic vulnerability.
  • Targeting the mevalonate pathway and macropinocytosis represents a promising strategy for cancer intervention.
Keywords:
cancerchemotaxismevalonate pathwaysmall GTPasestumor organoids

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