Protein kinase D drives the secretion of invasion mediators in triple-negative breast cancer cell lines
Alexia Gali,
Irene V. Bijnsdorp,
Sander R. Piersma,
Thang V. Pham,
Elena Gutiérrez-Galindo,
Fiona Kühnel,
Nikos Tsolakos,
Connie R. Jimenez,
Angelika Hausser,
Leonidas G. Alexopoulos
Affiliations
Alexia Gali
Biomedical Systems Laboratory, National Technical University of Athens, 15780 Athens, Greece; Protavio Ltd, Demokritos Science Park, 15341 Athens, Greece
Irene V. Bijnsdorp
Department of Urology, Cancer Center Amsterdam, Cancer Center Amsterdam, Amsterdam UMC, de Boelelaan 1117, Amsterdam 1081 HV, the Netherlands; Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, OncoProteomics Laboratory, de Boelelaan 1117, , Amsterdam 1081 HV, the Netherlands
Sander R. Piersma
Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, OncoProteomics Laboratory, de Boelelaan 1117, , Amsterdam 1081 HV, the Netherlands
Thang V. Pham
Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, OncoProteomics Laboratory, de Boelelaan 1117, , Amsterdam 1081 HV, the Netherlands
Elena Gutiérrez-Galindo
Institute of Cell Biology and Immunology, University of Stuttgart, 70569 Stuttgart, Germany
Fiona Kühnel
Institute of Cell Biology and Immunology, University of Stuttgart, 70569 Stuttgart, Germany
Nikos Tsolakos
Protavio Ltd, Demokritos Science Park, 15341 Athens, Greece
Connie R. Jimenez
Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, OncoProteomics Laboratory, de Boelelaan 1117, , Amsterdam 1081 HV, the Netherlands
Angelika Hausser
Institute of Cell Biology and Immunology, University of Stuttgart, 70569 Stuttgart, Germany; Stuttgart Research Center for Systems Biology, University of Stuttgart, 70569 Stuttgart, Germany; Corresponding author
Leonidas G. Alexopoulos
Biomedical Systems Laboratory, National Technical University of Athens, 15780 Athens, Greece; Protavio Ltd, Demokritos Science Park, 15341 Athens, Greece; Corresponding author
Summary: The protein kinase D (PKD) family members regulate the fission of cargo vesicles at the Golgi complex and play a pro-oncogenic role in triple-negative breast cancer (TNBC). Whether PKD facilitates the secretion of tumor-promoting factors in TNBC, however, is still unknown. Using the pharmacological inhibition of PKD activity and siRNA-mediated depletion of PKD2 and PKD3, we identified the PKD-dependent secretome of the TNBC cell lines MDA-MB-231 and MDA-MB-468. Mass spectrometry-based proteomics and antibody-based assays revealed a significant downregulation of extracellular matrix related proteins and pro-invasive factors such as LIF, MMP-1, MMP-13, IL-11, M-CSF and GM-CSF in PKD-perturbed cells. Notably, secretion of these proteins in MDA-MB-231 cells was predominantly controlled by PKD2 and enhanced spheroid invasion. Consistently, PKD-dependent secretion of pro-invasive factors was more pronounced in metastatic TNBC cell lines. Our study thus uncovers a novel role of PKD2 in releasing a pro-invasive secretome.
