Somatostatin receptor 2 signaling promotes growth and tumor survival in small-cell lung cancer.

Abstract

Somatostatin receptor 2 (SSTR2) is overexpressed in a majority of neuroendocrine neoplasms, including small-cell lung carcinomas (SCLCs). SSTR2 was previously considered an inhibitory receptor on cell growth, but its agonists had poor clinical responses in multiple clinical trials. The role of this receptor as a potential therapeutic target in lung cancer merits further investigation. We evaluated the expression of SSTR2 in a cohort of 96 primary tumors from patients with SCLC and found 48% expressed SSTR2. Correlation analysis in both CCLE and an SCLC RNAseq cohort confirmed high-level expression and identified an association between NEUROD1 and SSTR2. There was a significant association with SSTR2 expression profile and poor clinical outcome. We tested whether SSTR2 expression might contribute to tumor progression through activation of downstream signaling pathways, using in vitro and in vivo systems and downregulated SSTR2 expression in lung cancer cells by shRNA. SSTR2 downregulation led to increased apoptosis and dramatically decreased tumor growth in vitro and in vivo in multiple cell lines with decreased AMPKα phosphorylation and increased oxidative metabolism. These results demonstrate a role for SSTR2 signaling in SCLC and suggest that SSTR2 is a poor prognostic biomarker in SCLC and potential future therapeutic signaling target.

• Authors: Jonathan M Lehman, Megan D Hoeksema, Jeremy Staub, Jun Qian, Bradford Harris, J Clay Callison, Jennifer Miao, Chanjuan Shi, Rosana Eisenberg, Heidi Chen, Sheau-Chiann Chen, Pierre P Massion
• Journal: International journal of cancer (Int J Cancer) Vol. 144 Issue 5 Pg. 1104-1114 (03 01 2019) ISSN: 1097-0215 [Electronic] United States
• PMID: 30152518 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2018 UICC.

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Biomarkers, Tumor
• Nerve Tissue Proteins
• RNA, Messenger
• Receptors, Somatostatin
• SSTR2 protein, human
• Neurogenic differentiation factor 1
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (genetics)
• Animals
• Apoptosis (genetics)
• Basic Helix-Loop-Helix Transcription Factors (genetics)
• Biomarkers, Tumor (genetics)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Disease Progression
• Down-Regulation (genetics)
• Humans
• Lung Neoplasms (genetics, pathology)
• Mice
• Mice, Nude
• Nerve Tissue Proteins (genetics)
• RNA, Messenger (genetics)
• Receptors, Somatostatin (genetics)
• Signal Transduction (genetics)
• Small Cell Lung Carcinoma (genetics, pathology)