Journal article
RABL6A promotes G1-S phase progression and pancreatic neuroendocrine tumor cell proliferation in an Rb1-dependent manner
Cancer research (Chicago, Ill.), Vol.74(22), pp.6661-6670
11/15/2014
DOI: 10.1158/0008-5472.can-13-3742
PMCID: PMC4233153
PMID: 25273089
Abstract
Mechanisms of neuroendocrine tumor (NET) proliferation are poorly understood, and therapies that effectively control NET progression and metastatic disease are limited. We found amplification of a putative oncogene, RABL6A, in primary human pancreatic NETs (PNET) that correlated with high-level RABL6A protein expression. Consistent with those results, stable silencing of RABL6A in cultured BON-1 PNET cells revealed that it is essential for their proliferation and survival. Cells lacking RABL6A predominantly arrested in G1 phase with a moderate mitotic block. Pathway analysis of microarray data suggested activation of the p53 and retinoblastoma (Rb1) tumor-suppressor pathways in the arrested cells. Loss of p53 had no effect on the RABL6A knockdown phenotype, indicating that RABL6A functions independent of p53 in this setting. By comparison, Rb1 inactivation partially restored G1 to S phase progression in RABL6A-knockdown cells, although it was insufficient to override the mitotic arrest and cell death caused by RABL6A loss. Thus, RABL6A promotes G1 progression in PNET cells by inactivating Rb1, an established suppressor of PNET proliferation and development. This work identifies RABL6A as a novel negative regulator of Rb1 that is essential for PNET proliferation and survival. We suggest RABL6A is a new potential biomarker and target for anticancer therapy in PNET patients.
Details
- Title: Subtitle
- RABL6A promotes G1-S phase progression and pancreatic neuroendocrine tumor cell proliferation in an Rb1-dependent manner
- Creators
- Jussara Hagen - Department of Pharmacology, University of Iowa, Iowa City, IowaViviane P Muniz - Department of Pharmacology, University of Iowa, Iowa City, Iowa. Molecular and Cellular Biology Graduate Program, University of Iowa, Iowa City, IowaKelly C Falls - Medical Scientist Training Program, University of Iowa, Iowa City, IowaSara M Reed - Department of Pharmacology, University of Iowa, Iowa City, Iowa. Medical Scientist Training Program, University of Iowa, Iowa City, IowaAgshin F Taghiyev - Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, IowaFrederick W Quelle - Department of Pharmacology, University of Iowa, Iowa City, Iowa. The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IowaFrancoise A Gourronc - Department of Microbiology, College of Medicine, University of Iowa, Iowa City, IowaAloysius J Klingelhutz - Molecular and Cellular Biology Graduate Program, University of Iowa, Iowa City, Iowa. The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Microbiology, College of Medicine, University of Iowa, Iowa City, IowaHeather J Major - Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, IowaRyan W Askeland - Department of Pathology, College of Medicine, University of Iowa, Iowa City, IowaScott K Sherman - Department of Surgery, College of Medicine, University of Iowa, Iowa City, IowaThomas M O'Dorisio - The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Internal Medicine, College of Medicine, University of Iowa, Iowa City, IowaAndrew M Bellizzi - The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Pathology, College of Medicine, University of Iowa, Iowa City, IowaJames R Howe - The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Surgery, College of Medicine, University of Iowa, Iowa City, IowaBenjamin W Darbro - Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, Iowa. The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IowaDawn E Quelle - Department of Pharmacology, University of Iowa, Iowa City, Iowa. Molecular and Cellular Biology Graduate Program, University of Iowa, Iowa City, Iowa. Medical Scientist Training Program, University of Iowa, Iowa City, Iowa. The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Pathology, College of Medicine, University of Iowa, Iowa City, Iowa. dawn-quelle@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.74(22), pp.6661-6670
- DOI
- 10.1158/0008-5472.can-13-3742
- PMID
- 25273089
- PMCID
- PMC4233153
- NLM abbreviation
- Cancer Res
- ISSN
- 1538-7445
- eISSN
- 1538-7445
- Publisher
- United States
- Grant note
- R21-CA127031 / NCI NIH HHS T32 GM067795 / NIGMS NIH HHS R01-CA090367 / NCI NIH HHS T32 CA148062 / NCI NIH HHS T32 GM007337 / NIGMS NIH HHS R01 CA090367 / NCI NIH HHS 5T32-CA148062 / NCI NIH HHS R21 CA127031 / NCI NIH HHS P30-CA086862 / NCI NIH HHS P30 CA086862 / NCI NIH HHS
- Language
- English
- Date published
- 11/15/2014
- Academic Unit
- Molecular Physiology and Biophysics; Microbiology and Immunology; Stead Family Department of Pediatrics; Pathology; Medical Genetics and Genomics; Surgery; Radiation Oncology; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984001217202771
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