Research Papers:
Coordinated downregulation of Spinophilin and the catalytic subunits of PP1, PPP1CA/B/C, contributes to a worse prognosis in lung cancer
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Abstract
Eva M. Verdugo-Sivianes1,2, Lola Navas1,2, Sonia Molina-Pinelo1,2, Irene Ferrer2,3, Alvaro Quintanal-Villalonga3, Javier Peinado1,4, Jose M. Garcia-Heredia1,2,5, Blanca Felipe-Abrio1,2, Sandra Muñoz-Galvan1,2, Juan J. Marin1,2,6, Luis Montuenga2,7, Luis Paz-Ares2,3 and Amancio Carnero1,2
1Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Sevilla, Spain
2CIBER de Cáncer, Instituto de Salud Carlos III, Pabellón 11, Planta 0, Madrid, Spain
3H120-CNIO Lung Cancer Clinical Research Unit, Instituto de Investigación Hospital 12 de Octubre and CNIO, Madrid, Spain
4Radiation Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain
5Department of Vegetal Biochemistry and Molecular Biology, University of Seville, Seville, Spain
6Department of Predictive Medicine and Public Health, Universidad de Sevilla, Sevilla, Spain
7Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), Pamplona, Spain
Correspondence to:
Amancio Carnero, email: [email protected]
Keywords: Spinophilin; PP1; biomarker; lung cancer; therapy
Received: May 13, 2017 Accepted: September 03, 2017 Published: October 26, 2017
ABSTRACT
The scaffold protein Spinophilin (Spinophilin, PPP1R9B) is one of the regulatory subunits of phosphatase-1 (PP1), directing it to distinct subcellular locations and targets. The loss of Spinophilin reduces PP1 targeting to pRb, thereby maintaining higher levels of phosphorylated pRb. Spinophilin is absent or reduced in approximately 40% of human lung tumors, correlating with the malignant grade. However, little is known about the relevance of the coordinated activity or presence of Spinophilin and its reported catalytic partners in the prognosis of lung cancer. In the present work, we show that the downregulation of Spinophilin, either by protein or mRNA, is related to a worse prognosis in lung tumors. This effect is more relevant in squamous cell carcinoma, SCC, than in adenocarcinoma. Downregulation of Spinophilin is related to a decrease in the levels of its partners PPP1CA/B/C, the catalytic subunits of PP1. A decrease in these subunits is also related to prognosis in SCC and, in combination with a decrease in Spinophilin, are markers of a poor prognosis in these tumors. The analysis of the genes that correlate to Spinophilin in lung tumors showed clear enrichment in ATP biosynthesis and protein degradation GO pathways. The analysis of the response to several common and pathway-related drugs indicates a direct correlation between the Spinophilin/PPP1Cs ratio and the response to oxaliplatin and bortezomib. This finding indicates that this ratio may be a good predictive biomarker for the activity of the drugs in these tumors with a poor prognosis.
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