Altered expression of vesicular trafficking machinery in prostate cancer affects lysosomal dynamics and provides insight into the underlying biology and disease progression

• Published in: British journal of cancer Vol. 131; no. 8; pp. 1263 - 1278
• Main Authors: Nturubika, Bukuru D., Guardia, Carlos M., Gershlick, David C., Logan, Jessica M., Martini, Carmela, Heatlie, Jessica K., Lazniewska, Joanna, Moore, Courtney, Lam, Giang T., Li, Ka L., Ung, Ben S-Y, Brooks, Robert D., Hickey, Shane M., Bert, Andrew G., Gregory, Philip A., Butler, Lisa M., O’Leary, John J., Brooks, Douglas A., Johnson, Ian R. D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-11-2024; Nature Publishing Group
• Subjects: 631/67/589/466; 631/80/313/1624; 692/699/67/589/466; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line, Tumor; Cell migration; Cell Movement; Confocal microscopy; Disease Progression; Drug Resistance; Epidemiology; Gene expression; Gene Expression Regulation, Neoplastic; Gene regulation; Humans; Immunohistochemistry; LAMP-1 protein; Lysosomes; Lysosomes - metabolism; Male; Microscopy; Molecular Medicine; Oncology; Overexpression; Pathogenesis; Phenotypes; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Transport; siRNA
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-024-02829-x

Background
This study focuses on the role of lysosomal trafficking in prostate cancer, given the essential role of lysosomes in cellular homoeostasis.
Methods
Lysosomal motility was evaluated using confocal laser scanning microscopy of LAMP-1-transfected prostate cells and spot-tracking analysis. Expression of lysosomal trafficking machinery was evaluated in patient cohort databases and through immunohistochemistry on tumour samples. The roles of vesicular trafficking machinery were evaluated through over-expression and siRNA. The effects of R1881 treatment on lysosome vesicular trafficking was evaluated by RNA sequencing, protein quantification and fixed- and live-cell microscopy.
Results
Altered regulation of lysosomal trafficking genes/proteins was observed in prostate cancer tissue, with significant correlations for co-expression of vesicular trafficking machinery in Gleason patterns. The expression of trafficking machinery was associated with poorer patient outcomes. R1881 treatment induced changes in lysosomal distribution, number, and expression of lysosomal vesicular trafficking machinery in hormone-sensitive prostate cancer cells. Manipulation of genes involved in lysosomal trafficking events induced changes in lysosome positioning and cell phenotype, as well as differential effects on cell migration, in non-malignant and prostate cancer cells.
Conclusions
These findings provide novel insights into the altered regulation and functional impact of lysosomal vesicular trafficking in prostate cancer pathogenesis.