Targeting Gastrin-releasing Peptide in Neuroblastoma

Abstract

The overall survival for neuroblastoma remains dismal, in part due to the emergence of resistance to chemotherapeutic drugs resulting in aggressive, refractory disease. As a neuroendocrine tumor, neuroblastomas secrete a number of peptides; one such being the gastrin-releasing peptide (GRP). GRP antagonists have been used to inhibit the proliferation of cancer cells. Here, I demonstrate that GRP silencing induced apoptosis in neuroblastoma cells and, in combination, allowed the usage of sublethal doses of chemotherapeutic drugs to elicit responses similar to lethal doses of the same drugs when used alone. GRP silencing also decreased tumorigenesis in vitro and suppressed liver metastasis in vivo. Moreover, GRP silencing increased PTEN levels with a simultaneous inhibition of AKT/mTOR/FAK activation in neuroblastoma cells. Interestingly, PTEN overexpression inhibited GRP-mediated neuroblastoma progression in vitro. This placed PTEN as a critical negative regulator of the oncogenic effects of GRP in neuroblastoma progression. This study provides a rationale for the use of GRP antagonists in patients with aggressive, refractory neuroblastomas.