Splice variant of growth hormone-releasing hormone receptor drives esophageal squamous cell carcinoma conferring a therapeutic target

Proc Natl Acad Sci U S A. 2020 Mar 24;117(12):6726-6732. doi: 10.1073/pnas.1913433117. Epub 2020 Mar 10.

Abstract

The extrahypothalamic growth hormone-releasing hormone (GHRH) and its cognate receptors (GHRH-Rs) and splice variants are expressed in a variety of cancers. It has been shown that the pituitary type of GHRH-R (pGHRH-R) mediates the inhibition of tumor growth induced by GHRH-R antagonists. However, GHRH-R antagonists can also suppress some cancers that do not express pGHRH-R, yet the underlying mechanisms have not been determined. Here, using human esophageal squamous cell carcinoma (ESCC) as a model, we were able to reveal that SV1, a known splice variant of GHRH-R, is responsible for the inhibition induced by GHRH-R antagonist MIA-602. We demonstrated that GHRH-R splice variant 1 (SV1) is a hypoxia-driven promoter of tumor progression. Hypoxia-elevated SV1 activates a key glycolytic enzyme, muscle-type phosphofructokinase (PFKM), through the nuclear factor kappa B (NF-κB) pathway, which enhances glycolytic metabolism and promotes progression of ESCC. The malignant actions induced by the SV1-NF-κB-PFKM pathway could be reversed by MIA-602. Altogether, our studies demonstrate a mechanism by which GHRH-R antagonists target SV1. Our findings suggest that SV1 is a hypoxia-induced oncogenic promoter which can be an alternative target of GHRH-R antagonists.

Keywords: GHRH-R antagonist; PFKM; glycolysis; hypoxia; splicing isoform of GHRH-R.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alternative Splicing
  • Animals
  • Apoptosis
  • Biomarkers, Tumor / genetics*
  • Cell Proliferation
  • Esophageal Neoplasms / genetics
  • Esophageal Neoplasms / metabolism
  • Esophageal Neoplasms / pathology*
  • Esophageal Squamous Cell Carcinoma / genetics
  • Esophageal Squamous Cell Carcinoma / metabolism
  • Esophageal Squamous Cell Carcinoma / pathology*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Glycolysis
  • Humans
  • Mice
  • Mice, Nude
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Phosphofructokinase-1, Muscle Type / genetics
  • Phosphofructokinase-1, Muscle Type / metabolism
  • Receptors, LHRH / antagonists & inhibitors
  • Receptors, LHRH / genetics*
  • Sermorelin / analogs & derivatives*
  • Sermorelin / pharmacology
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • GHRH(1-29)NH2, (PhAc-Ada)(0)-Tyr(1), Arg(2), Fpa(5,6), Ala(8), Har(9), Tyr(Me)(10), His(11), Orn(12,) Abu(15), His(20), Orn(21), Nle(27), Arg(28), Har(29)-
  • NF-kappa B
  • Receptors, LHRH
  • Sermorelin
  • Phosphofructokinase-1, Muscle Type
  • PFKM protein, human