Neuropeptide G Protein-Coupled Receptors as Oncotargets

Abstract

Neuropeptide G protein-coupled receptors (GPCRs) are overexpressed on numerous cancer cells. In a number of tumors, such as small cell lung cancer (SCLC), bombesin (BB) like peptides and neurotensin (NTS) function as autocrine growth factors whereby they are secreted from tumor cells, bind to cell surface receptors and stimulate growth. BB-drug conjugates and BB receptor antagonists inhibit the growth of a number of cancers. Vasoactive intestinal peptide (VIP) increases the secretion rate of BB-like peptide and NTS from SCLC leading to increased proliferation. In contrast, somatostatin (SST) inhibits the secretion of autocrine growth factors from neuroendocrine tumors (NETs) and decreases proliferation. SST analogs such as radiolabeled octreotide can be used to localize tumors, is therapeutic for certain cancer patients and has been approved for four different indications in the diagnosis/treatment of NETs. The review will focus on how BB, NTS, VIP, and SST receptors can facilitate the early detection and treatment of cancer.

Keywords: bombesin; cancer GPCR; cancer RTK; cancer signal transduction; neurotensin; pituitary adenylate cyclase activating polypeptide (PACAP); somatostatin; vasoactive intestinal peptide.

Figure 1

Effect of GPCR's on RTK transactivation. GPCRs for BB and NTS couple to Gq and causes metabolism of PIP₂ to DAG (activates PKC) and IP₃ (elevates cytosolic Ca²⁺). Addition of NTS or BB to NSCLC cells increases phosphorylation of PYK2, FAK or paxillin leading to increased cellular migration. GPCR for VIP interact with Gs activating adenylyl cyclase and increasing cAMP. The cAMP activates PKA leading to CREB phosphorylation and altered gene expression. GPCR for PACAP interact with both Gq and Gs. GPCR activate Src and MMP resulting in the production of EGFR ligands such as TGFα. When TGFα binds to the EGFR, tyrosine kinase activity is increased leading to phosphorylated EGFR homodimers or EGFR-HER2 heterodimers. The RTK activates the Ras-Raf-MEK-ERK pathway leading to increased cellular proliferation. The RTK activates the PI3K-PKD-AKT-mTOR pathway leading to increased cellular survival. The phosphorylated EGFR/HER2 is dephosphorylated by protein tyrosine phosphatase (PTP).

Figure 2

Structures of SST and synthetic analogs used clinically. (A) The 14 amino acid SST is shown and essential amino acids are in black. The SST synthetic analogs, octreotide (B), and lanreotide (C), which have 8 amino acids, are approved to treat patients with neuroendocrine tumors (NETs) producing hormone-excess states (VIPoma, carcinoid syndrome) and for their anti-proliferative activity in patients with advanced, aggressive NETs. ¹¹¹InDTPA pentetreotide (D) as well as ⁶⁸GaDOTATATE (E) are used for SSTR imaging in patients with NETs. ⁹⁰Y-DOTA (F) and ¹⁷⁷Lu-DOTA (G) -labeled SST analogs are used for their antitumor activity during PRRT by targeting the cytotoxic radiolabel to the tumor.