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GNAS mutation inhibits growth and induces phosphodiesterase 4D expression in colorectal cancer cell lines

Pirjo Nummela1,2, Sadia Zafar1,2, Erika Veikkolainen1,2

  • 1Applied Tumor Genomics Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.

International Journal of Cancer
|February 6, 2024
PubMed

Insights

Activating GNAS mutations in colorectal cancer (CRC) slow tumor cell growth and increase PDE4D. PDE4 inhibitors may impede proliferation in GNAS-mutated CRC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Activating GNAS mutations occur in ~5% of colorectal cancers (CRCs).
  • These mutations activate cAMP signaling and are linked to poor prognosis.
  • The precise impact of GNAS mutations on CRC biology requires further elucidation.

Purpose of the Study:

  • To investigate the functional consequences of activating GNAS mutations in CRC.
  • To analyze gene expression changes, cell proliferation, and tumor growth in GNAS-mutated CRC models.
  • To explore PDE4D as a therapeutic target in GNAS-mutated CRC.

Main Methods:

  • Utilized GNAS-mutated (GNASmt) and parental (Par) HCT116 CRC cell lines.
  • Performed RNA sequencing to identify differentially expressed genes.
  • Assessed cell proliferation in vitro and tumor growth in vivo in mouse models.
  • Tested the effects of PDE4 inhibitors (Ro 20-1724 and GEBR-7b) on cell proliferation.

Main Results:

  • GNASmt HCT116 cells exhibited increased cAMP synthesis and slower proliferation compared to Par cells.
  • RNA sequencing revealed PDE4D as the most upregulated gene in GNASmt cells.
  • Human CRC tumors showed PDE4D overexpression in GNAS mutant cases.
  • PDE4 inhibitors suppressed GNASmt cell proliferation, with similar effects observed in SK-CO-1 CRC cells.
  • In vivo, GNASmt cells formed smaller tumors in nude mice.

Conclusions:

  • GNAS mutations paradoxically lead to growth suppression in colorectal cancer cells.
  • GNAS mutation-induced PDE4D overexpression presents a potential therapeutic vulnerability.
  • Targeting PDE4 with inhibitors may offer a strategy to impede GNAS-mutated CRC proliferation.
Keywords:
GNASPDE4cAMPcolorectal cancerphosphodiesterase

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