SEMA3C drives cancer growth by transactivating multiple receptor tyrosine kinases via Plexin B1

EMBO Mol Med. 2018 Feb;10(2):219-238. doi: 10.15252/emmm.201707689.

Abstract

Growth factor receptor tyrosine kinase (RTK) pathway activation is a key mechanism for mediating cancer growth, survival, and treatment resistance. Cognate ligands play crucial roles in autocrine or paracrine stimulation of these RTK pathways. Here, we show SEMA3C drives activation of multiple RTKs including EGFR, ErbB2, and MET in a cognate ligand-independent manner via Plexin B1. SEMA3C expression levels increase in castration-resistant prostate cancer (CRPC), where it functions to promote cancer cell growth and resistance to androgen receptor pathway inhibition. SEMA3C inhibition delays CRPC and enzalutamide-resistant progression. Plexin B1 sema domain-containing:Fc fusion proteins suppress RTK signaling and cell growth and inhibit CRPC progression of LNCaP xenografts post-castration in vivo SEMA3C inhibition represents a novel therapeutic strategy for treatment of advanced prostate cancer.

Keywords: Plexin B1; Semaphorin 3C; apoptosis; prostate cancer; receptor tyrosine kinase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Humans
  • Male
  • Mice
  • Nerve Tissue Proteins / metabolism*
  • Prostatic Neoplasms, Castration-Resistant / metabolism*
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptors, Cell Surface / metabolism*
  • Semaphorins / antagonists & inhibitors
  • Semaphorins / metabolism*
  • Signal Transduction
  • Xenograft Model Antitumor Assays

Substances

  • Nerve Tissue Proteins
  • PLXNB1 protein, human
  • Receptors, Cell Surface
  • Sema3C protein, human
  • Semaphorins
  • Receptor Protein-Tyrosine Kinases