Loss of CDCP1 triggers FAK activation in detached prostate cancer cells.

A major metastasis suppressing mechanism is the rapid apoptotic death of cancer cells upon detachment from extracellular matrix, a process called anoikis. Focal adhesion kinase (PTK2/FAK) is a key enzyme involved in evasion of anoikis. We show that loss of the Cub-domain containing protein-1 (CDCP1), paradoxically stimulates FAK activation in the detached state of prostate cancer cells. In CDCP1low DU145 and PC3 prostate cancer cells, detachment-activation of FAK occurs through local production of PI(4,5)P2. PI(4,5)P2 is generated by the PIP5K1c-201 splicing isoform of PIP5K1c, which contains a unique SRC phosphorylation site. In the detached state, reduced expression of CDCP1 and an alternative CDCP1-independent SRC activation mechanism triggers PIP5K1c-pY644 phosphorylation by SRC. This causes a switch of Talin binding from β1-integrin to PIP5K1c-pY644 and leads to activation of PIP5K1c-FAK. Reduced CDCP1 expression also inactivates CDK5, a negative regulator of PIP5K1c. Furthermore, immersion of prostate cancer cells in 10% human plasma or fetal bovine serum is required for activation of PIP5K1c-FAK. The PIP5K1c induced detachment-activation of FAK in preclinical models sensitizes CDCP1low prostate cancer cells to FAK inhibitors. In patients, CDCP1High versus CDCP1low circulating tumor cells differ in expression of AR-v7, ONECUT2 and HOXB13 oncogenes and TMPRSS2 and display intra-patient heterogeneity of FAK-pY397 expression. Taken together, CDCP1low and CDCP1high detached prostate cancer cells activate distinct cytoplasmic kinase complexes and targetable transcription factors, which has important therapeutic implications.

American journal of clinical and experimental urology. 2021 Aug 25*** epublish ***

Sara G Pollan, Pai-Chi Teng, Yu Jen Jan, Julie Livingstone, Cai Huang, Minhyung Kim, Javier Mariscal, Maria Rodriguez, Jie-Fu Chen, Sungyong You, Dolores DiVizio, Paul C Boutros, Keith Syson Chan, Olga Rasorenova, Anne Cress, Danislav Spassov, Mark Moasser, Edwin M Posadas, Stephen J Freedland, Michael R Freeman, Jie J Zheng, Beatrice S Knudsen

Department of Surgery, Cedars-Sinai Medical Center 8700 Beverly Blvd, Los Angeles, CA 90048, USA., Department of Informatics and Biocomputing, Ontario Institute for Cancer Research Toronto, ON M5G 1L7, Canada., Department of Pharmacology and Nutritional Sciences, Markey Cancer Center, University of Kentucky 789 South Limestone St, Lexington, KY 40536, USA., Department of Human Genetics and Urology, Jonsson Comprehensive Cancer Centre, University of California Los Angeles, CA, USA., Department of Pathology, Cedars-Sinai Medical Center 8700 Beverly Blvd, Los Angeles, CA 90048, USA., Department of Molecular Biology and Biochemistry, University of California Irvine Irvine, CA 92697, USA., Department of Cellular and Molecular Medicine, University of Arizona College of Medicine 1501 N, Campbell Avenue, Tucson, AZ 85724, USA., Department of Medicine, University of California San Francisco San Francisco, CA 94143, USA., Department of Medicine, Cedars-Sinai Medical Center 8700 Beverly Blvd, Los Angeles, CA 90048, USA., Department of Cell & Developmental Biology, University of California Los Angeles CHS BH-973B, Los Angeles, CA 90095, USA., Department of Biomedical Sciences, Cedars-Sinai Medical Center 8700 Beverly Blvd, Los Angeles, CA 90048, USA.

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