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

Xiao Xiong, Xiurong Ke, Lu Wang, Zhimeng Yao, Yi Guo, Xianyang Zhang, Yuping Chen, Chi Pui Pang, Andrew V. Schally, Hao Zhang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6726-6732
Number of pages7
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number12
DOIs
StatePublished - Mar 24 2020

Keywords

  • GHRH-R antagonist
  • Glycolysis
  • Hypoxia
  • PFKM
  • Splicing isoform of GHRH-R

ASJC Scopus subject areas

  • General

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