Open Access
27-hydroxycholesterol impairs plasma membrane lipid raft signaling as evidenced by inhibition of IL6-JAK-STAT3 signaling in prostate cancer cells
(American Association for Cancer Research, 2020-05-01) Dambal, Shweta; Alfaqih, Mahmoud; Sanders, Sergio; Maravilla, Erick; Ramírez-Torres, Adela; Galván, Gloria C.; Reis-Sobreiro, Mariana; Rotinen Díaz, Mirja Sofia; Driver, Lucy M.; Behrove, Matthew. S.; Talisman, Tijana Jovanovic; Yoon, Junhee; You, Sungyong; Turkson, James; Chi, Jen-Tsan; Freeman, Michael R.; Macías, Everardo; Freedland, Stephen J.; Ciencias de la Salud; Osasun Zientziak
We recently reported that restoring the CYP27A1-27hydroxycholesterol axis had antitumor properties. Thus, we sought to determine the mechanism by which 27HC exerts its anti-prostate cancer effects. As cholesterol is a major component of membrane microdomains known as lipid rafts, which localize receptors and facilitate cellular signaling, we hypothesized 27HC would impair lipid rafts, using the IL6-JAK-STAT3 axis as a model given its prominent role in prostate cancer. As revealed by single molecule imaging of DU145 prostate cancer cells, 27HC treatment significantly reduced detected cholesterol density on the plasma membranes. Further, 27HC treatment of constitutively active STAT3 DU145 prostate cancer cells reduced STAT3 activation and slowed tumor growth in vitro and in vivo. 27HC also blocked IL6-mediated STAT3 phosphorylation in nonconstitutively active STAT3 cells. Mechanistically, 27HC reduced STAT3 homodimerization, nuclear translocation, and decreased STAT3 DNA occupancy at target gene promoters. Combined treatment with 27HC and STAT3 targeting molecules had additive and synergistic effects on proliferation and migration, respectively. Hallmark IL6-JAK-STAT gene signatures positively correlated with CYP27A1 gene expression in a large set of human metastatic castrate-resistant prostate cancers and in an aggressive prostate cancer subtype. This suggests STAT3 activation may be a resistance mechanism for aggressive prostate cancers that retain CYP27A1 expression. In summary, our study establishes a key mechanism by which 27HC inhibits prostate cancer by disrupting lipid rafts and blocking STAT3 activation. IMPLICATIONS: Collectively, these data show that modulation of intracellular cholesterol by 27HC can inhibit IL6-JAK-STAT signaling and may synergize with STAT3-targeted compounds.
Open Access
Scaffold attachment factor B1 regulates androgen degradation pathways in prostate cancer
(E-Century Publishing, 2021) Yang, Julie Suan-Wei; Qian, Chen; You, Sungyong; Rotinen Díaz, Mirja Sofia; Posadas, Edwin M.; Freedland, Stephen J.; Di Vizio, Dolores; Kim, Jayoung; Freeman, Michael R.; Ciencias de la Salud; Osasun Zientziak
The nuclear matrix protein Scaffold Attachment Factor B1 (SAFB1, SAFB) can act in prostate cancer (PCa) as an androgen receptor (AR) co-repressor that functions through epigenetic silencing of AR targets, such as prostate specific antigen (PSA, KLK3). Genomic profiling of SAFB1-silenced PCa cells indicated that SAFB1 may play a role in modulating intracrine androgen levels through the regulation of UDP-glucuronosyltransferase (UGT) genes, which inactivate steroid hormones. Gene silencing of SAFB1 resulted in increased levels of free dihydrotesterosterone (DHT), and increased resistance to the AR inhibitor enzalutamide. SAFB1 silencing suppressed expression of the UDP-glucuronosyltransferase family 2 member B15 gene (UGT2B15) and the closely related UGT2B17 gene, which encode proteins that irreversibly inactivate testosterone (T) and DHT. Analysis of human data indicated that genomic loss at the SAFB locus, or down-regulation of expression of the SAFB gene, is associated with aggressive PCa. These findings identify SAFB1 as an important regulator of androgen catabolism in PCa and suggest that loss or inactivation of this protein may promote AR activity by retention of active androgen in tumor cells.
Open Access
Large oncosomes in human prostate cancer tissues and in the circulation of mice with metastatic disease
(Elsevier, 2012-11-01) Di Vizio, Dolores; Morello, Matteo; Dudley, Andrew C.; Schow, Peter W.; Adam, Rosalyn M.; Morley, Samantha; Mulholland, David; Rotinen Díaz, Mirja Sofia; Hager, Martin H.; Insabato, Luigi; Moses, Marsha A.; Demichelis, Francesca; Lisanti, Michael P.; Wu, Hong; Klagsbrun, Michael; Bhowmick, Neil A.; Rubin, Mark A.; D'Souza-Schorey, Crislyn; Freeman, Michael R.; Ciencias de la Salud; Osasun Zientziak
Oncosomes are tumor-derived microvesicles that transmit signaling complexes between cell and tissue compartments. Herein, we show that amoeboid tumor cells export large (1- to 10-μm diameter) vesicles, derived from bulky cellular protrusions, that contain metalloproteinases, RNA, caveolin-1, and the GTPase ADP-ribosylation factor 6, and are biologically active toward tumor cells, endothelial cells, and fibroblasts. We describe methods by which large oncosomes can be selectively sorted by flow cytometry and analyzed independently of vesicles <1 μm. Structures resembling large oncosomes were identified in the circulation of different mouse models of prostate cancer, and their abundance correlated with tumor progression. Similar large vesicles were also identified in human tumor tissues, but they were not detected in the benign compartment. They were more abundant in metastases. Our results suggest that tumor microvesicles substantially larger than exosome-sized particles can be visualized and quantified in tissues and in the circulation, and isolated and characterized using clinically adaptable methods. These findings also suggest a mechanism by which migrating tumor cells condition the tumor microenvironment and distant sites, thereby potentiating advanced disease.
Open Access
Targeting key players of neuroendocrine differentiation in prostate cancer
(MDPI, 2023) Zamora Álvarez, Irene; Freeman, Michael R.; Encío Martínez, Ignacio; Rotinen Díaz, Mirja Sofia; Ciencias de la Salud; Osasun Zientziak
Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer (PC) that commonly emerges through a transdifferentiation process from prostate adenocarcinoma and evades conventional therapies. Extensive molecular research has revealed factors that drive lineage plasticity, uncovering novel therapeutic targets to be explored. A diverse array of targeting agents is currently under evaluation in pre-clinical and clinical studies with promising results in suppressing or reversing the neuroendocrine phenotype and inhibiting tumor growth and metastasis. This new knowledge has the potential to contribute to the development of novel therapeutic approaches that may enhance the clinical management and prognosis of this lethal disease. In the present review, we discuss molecular players involved in the neuroendocrine phenotype, and we explore therapeutic strategies that are currently under investigation for NEPC.

Rotinen Díaz, Mirja Sofia

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