BI-015 a novel diagnostic and prognostic prostate cancer biomarker that buffers the translational burden of neoplastic transformation


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Hayley Whitaker1,2, Jonathan Kay1, Anne Warren3, Ian Mills11, Benjamin Thomas1, Fredrik Wiklund5, Amanda Seipel4, Dan Berney6, Lars Egevad4, Gabrielle Fisher7, Chris Foster8, Colin Cooper10, Peter Scardino9, Jack Cuzick7, Henrik Gronberg5, David Neal1
1Uro-Oncology Group, Cancer Research UK Cambridge Institute, Cambridge, UK, 2Biomarker Initiative, Cancer Research UK Cambridge Institute, Cambridge, UK, 3Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK, 4Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden, 5Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden, 6The Orchid Tissue Laboratory, Centre for Molecular Oncology, Barts and The London School of Medicine and Dentistry, London, UK, 7Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, St Bartholomew’s Medical School, Queen Mary, University of London, London, UK, 8Department of Cellular Pathology and Molecular Genetics, Liverpool University Hospital, Liverpool, UK, 9Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, USA, 10Institute of Cancer, The Royal Marsden Hospital, Sutton, UK, 11Centre for Molecular Medicine, Oslo, Norway

Background

The molecular background that determines a patient's ability to respond positively to differing treatment regimes is driving translational research to develop new biomarkers for prostate cancer. Cell transformation introduces new metabolic and translational pressures that the cell must overcome to survive. Excessive levels of new proteins, that would otherwise be toxic to the cell, are processed by inducing the stress response pathway, autophagy or secretion. Here we present the 350 kDa BI-015 protein as a novel regulator of protein translation and secretion that acts as a predictive and diagnostic biomarker of the disease.

Method

BI-015 expression was quantified using immunohistochemistry in three independent tissue microarrays, with extensive clinical follow up. A stably transfected LNCaP cell line with attenuated BI-015 expression was generated to elucidate the function of the protein. Network analysis revealed an association of BI-015 with c-myc driven pathways that regulate translation (mTOR, EIFE) and aminoacyl-tRNA biosynthesis.

Results

BI-015 was expressed in the luminal epithelial cells of prostate tumours but was absent in benign tissue. BI-015 expression predicted patient outcome, with high expression doubling the likelihood of recurrence within 5 years following radical prostectomy (HR=2.2, p value=0.01). In human tissue and LNCaP cells BI-015 localised to distinct vesicle structures, suggesting a role in vesicle transport. BI-015 positive vesicles colocalised with components of the Golgi apparatus and fused with lysosomes in a calcium dependent manner. Cells with reduced BI-015 expression showed lower rates of protein translation and secretion of PSA.

Conclusion

BI-015 is a novel predictive and diagnostic biomarker of prostate cancer that regulates protein translation and secretion of PSA. Therapeutic targeting of BI-015 in cancer may prevent cells overcoming the burden of increasing translation with neoplastic transformation, and result in cell death.