Prostate cancer cell-platelet bidirectional signaling promotes calcium mobilization, invasion and apoptotic resistance via distinct receptor-ligand pairs

Authors

Kaitlin Garofano, Department of Pharmacology and Physiology, George Washington University, 2300 I Street NW, Washington, DC, 20037, USA.
Kameron Rashid, Department of Pharmacology and Physiology, George Washington University, 2300 I Street NW, Washington, DC, 20037, USA.
Michael Smith, Department of Pharmacology and Physiology, George Washington University, 2300 I Street NW, Washington, DC, 20037, USA.
Christine Brantner, GW Nanofabrication and Imaging Center, The George Washington University, Washington, DC, 20037, USA.
Sumanun Suwunnakorn, Department of Microbiology Immunology and Tropical Medicine, The George Washington University, Washington, DC, 20037, USA.
David Diemert, Department of Medicine, George Washington University, Washington, DC, 20037, USA.
Olivia Gordon, Department of Pharmacology and Physiology, George Washington University, 2300 I Street NW, Washington, DC, 20037, USA.
Anelia Horvath, Department of Biochemistry and Molecular Medicine, George Washington University, Washington, DC, 20037, USA.
Sikandar Khan, Department of Pharmacology and Physiology, George Washington University, 2300 I Street NW, Washington, DC, 20037, USA.
Anastas Popratiloff, GW Nanofabrication and Imaging Center, The George Washington University, Washington, DC, 20037, USA.
Johng Rhim, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
Alfateh Sidahmed, Department of Medicine, George Washington University, Washington, DC, 20037, USA.
Sanjay B. Maggirwar, Department of Microbiology Immunology and Tropical Medicine, The George Washington University, Washington, DC, 20037, USA.
Travis J. O'Brien, Department of Pharmacology and Physiology, George Washington University, 2300 I Street NW, Washington, DC, 20037, USA.
Minoli A. Perera, Department of Pharmacology and Center for Pharmacogenomics, Northwestern University, Chicago, IL, 60611, USA.
Norman H. Lee, Department of Pharmacology and Physiology, George Washington University, 2300 I Street NW, Washington, DC, 20037, USA. nhlee@gwu.edu.

Document Type

Journal Article

Publication Date

2-17-2023

Journal

Scientific reports

Volume

13

Issue

1

DOI

10.1038/s41598-023-29450-x

Abstract

Platelets play a crucial role in cancer and thrombosis. However, the receptor-ligand repertoire mediating prostate cancer (PCa) cell-platelet interactions and ensuing consequences have not been fully elucidated. Microvilli emanating from the plasma membrane of PCa cell lines (RC77 T/E, MDA PCa 2b) directly contacted individual platelets and platelet aggregates. PCa cell-platelet interactions were associated with calcium mobilization in platelets, and translocation of P-selectin and integrin αβ onto the platelet surface. PCa cell-platelet interactions reciprocally promoted PCa cell invasion and apoptotic resistance, and these events were insensitive to androgen receptor blockade by bicalutamide. PCa cells were exceedingly sensitive to activation by platelets in vitro, occurring at a PCa cell:platelet coculture ratio as low as 1:10 (whereas PCa patient blood contains 1:2,000,000 per ml). Conditioned medium from cocultures stimulated PCa cell invasion but not apoptotic resistance nor platelet aggregation. Candidate transmembrane signaling proteins responsible for PCa cell-platelet oncogenic events were identified by RNA-Seq and broadly divided into 4 major categories: (1) integrin-ligand, (2) EPH receptor-ephrin, (3) immune checkpoint receptor-ligand, and (4) miscellaneous receptor-ligand interactions. Based on antibody neutralization and small molecule inhibitor assays, PCa cell-stimulated calcium mobilization in platelets was found to be mediated by a fibronectin1 (FN1)-αβ signaling axis. Platelet-stimulated PCa cell invasion was facilitated by a CD55-adhesion G protein coupled receptor E5 (ADGRE5) axis, with contribution from platelet cytokines CCL3L1 and IL32. Platelet-stimulated PCa cell apoptotic resistance relied on ephrin-EPH receptor and lysophosphatidic acid (LPA)-LPA receptor (LPAR) signaling. Of participating signaling partners, FN1 and LPAR3 overexpression was observed in PCa specimens compared to normal prostate, while high expression of CCR1 (CCL3L1 receptor), EPHA1 and LPAR5 in PCa was associated with poor patient survival. These findings emphasize that non-overlapping receptor-ligand pairs participate in oncogenesis and thrombosis, highlighting the complexity of any contemplated clinical intervention strategy.

APA Citation

Garofano, Kaitlin; Rashid, Kameron; Smith, Michael; Brantner, Christine; Suwunnakorn, Sumanun; Diemert, David; Gordon, Olivia; Horvath, Anelia; Khan, Sikandar; Popratiloff, Anastas; Rhim, Johng; Sidahmed, Alfateh; Maggirwar, Sanjay B.; O'Brien, Travis J.; Perera, Minoli A.; and Lee, Norman H., "Prostate cancer cell-platelet bidirectional signaling promotes calcium mobilization, invasion and apoptotic resistance via distinct receptor-ligand pairs" (2023). GW Authored Works. Paper 2385.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/2385

Department

Pharmacology and Physiology