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Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
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The proprotein convertase furin is a pro-oncogenic driver in KRAS and BRAF driven colorectal cancer

Zongsheng He1, Lieven Thorrez2, Geraldine Siegfried3

  • 1Laboratory of Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium.

Oncogene
|March 7, 2020
PubMed

Insights

Furin inactivation suppresses colorectal cancer growth in KRAS or BRAF-mutant cells by blocking key oncogenic pathways. This identifies furin as a promising therapeutic target for personalized cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Activating mutations in KRAS and BRAF are common in colorectal cancer (CRC) and confer resistance to targeted therapies.
  • The ERK-MAPK pathway is frequently activated in CRC, driving tumor progression and therapeutic resistance.
  • Simultaneous targeting of multiple signaling pathways is needed for effective CRC treatment.

Purpose of the Study:

  • To investigate the role of the proprotein convertase furin in KRAS or BRAF-mutant CRC.
  • To determine if furin inactivation can suppress tumorigenesis in CRC with KRAS or BRAF mutations.
  • To identify furin as a potential therapeutic target for personalized CRC treatment.

Main Methods:

  • Genetic inactivation of furin in KRAS or BRAF-mutant and wild-type CRC cell lines.
  • Assessment of tumor growth, proliferation, migration, angiogenesis, and apoptosis in vitro and in a mouse xenograft model.
  • Analysis of protein precursor processing, ERK-MAPK pathway activity, and gene expression (e.g., PTGS2).
  • Correlation analysis of furin and KRAS/BRAF expression in human colorectal tumor samples.

Main Results:

  • Genetic inactivation of furin suppressed tumor growth, proliferation, and migration in KRAS or BRAF-mutant CRC cells, but not in wild-type cells.
  • Furin-deficient KRAS or BRAF-mutant cells showed reduced growth, angiogenesis, and increased apoptosis in vivo.
  • Furin inactivation prevented processing of oncogenic protein precursors (proIGF1R, proIR, proc-MET, proTGF-β1, NOTCH1), leading to sustained ERK-MAPK pathway suppression.
  • PTGS2, an ERK-MAPK activator, was downregulated in furin-inactivated mutant cells but upregulated in wild-type cells.
  • Human CRC samples showed a positive correlation between furin and KRAS/BRAF expression.

Conclusions:

  • Furin plays a critical role in KRAS or BRAF-driven ERK-MAPK pathway activation and tumorigenesis in CRC.
  • Targeting furin offers a potential strategy for personalized therapy in patients with KRAS or BRAF-mutant CRC.
  • Furin inactivation disrupts multiple oncogenic signaling pathways, providing a durable therapeutic effect.

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