STAT3 regulated ARF expression suppresses prostate cancer metastasis

Abstract Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19ARF as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF–Mdm2–p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14ARF expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

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RIPK2 Stabilizes c-Myc and is an Actionable Target for Inhibiting Prostate Cancer Metastasis

10.1101/2020.05.14.096867 ◽

2020 ◽

Author(s):

Yiwu Yan ◽

Bo Zhou ◽

Chen Qian ◽

Alex Vasquez ◽

Avradip Chatterjee ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Drug Targets ◽

Cancer Metastasis ◽

Therapeutic Interventions ◽

Interacting Protein ◽

Prostate Cancer Metastasis ◽

Prostate Cancers

AbstractDespite advances in diagnosis and treatment, metastatic prostate cancer remains incurable and is associated with high mortality rates. Thus, novel actionable drug targets are urgently needed for therapeutic interventions in advanced prostate cancer. Here we report receptor-interacting protein kinase 2 (RIPK2) as an actionable drug target for suppressing prostate cancer metastasis. RIPK2 is frequently amplified in lethal prostate cancers and its overexpression is associated with disease progression and aggressiveness. Genetic and pharmacological inhibition of RIPK2 significantly suppressed prostate cancer progression in vitro and metastasis in vivo. Multi-level proteomic analysis revealed that RIPK2 strongly regulates c-Myc protein stability and activity, largely by activating the MKK7/JNK/c-Myc phosphorylation pathway—a novel, non-canonical RIPK2 signaling pathway. Targeting RIPK2 inhibits this phosphorylation pathway, and thus promotes the degradation of c-Myc—a potent oncoprotein for which no drugs have been approved for clinical use yet. These results support targeting RIPK2 for personalized therapy in prostate cancer patients towards improving survival.

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EphA6 promotes angiogenesis and prostate cancer metastasis and is associated with human prostate cancer progression

Oncotarget ◽

10.18632/oncotarget.4088 ◽

2015 ◽

Vol 6 (26) ◽

pp. 22587-22597 ◽

Cited By ~ 22

Author(s):

Shibao Li ◽

Yingyu Ma ◽

Chongwei Xie ◽

Zhiyuan Wu ◽

Zhihua Kang ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Cancer Metastasis ◽

Human Prostate ◽

Human Prostate Cancer ◽

Prostate Cancer Progression ◽

Prostate Cancer Metastasis

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Activation of the RalGEF/Ral Pathway Promotes Prostate Cancer Metastasis to Bone

Molecular and Cellular Biology ◽

10.1128/mcb.00955-07 ◽

2007 ◽

Vol 27 (21) ◽

pp. 7538-7550 ◽

Cited By ~ 80

Author(s):

JuanJuan Yin ◽

Claire Pollock ◽

Kirsten Tracy ◽

Monika Chock ◽

Philip Martin ◽

...

Keyword(s):

Prostate Cancer ◽

Signaling Pathways ◽

Cell Line ◽

Cancer Progression ◽

Cancer Metastasis ◽

Receptor Activation ◽

Organ Specificity ◽

Tyrosine Kinase Receptor ◽

Nucleotide Exchange ◽

Prostate Cancer Metastasis

ABSTRACT A hallmark of metastasis is organ specificity; however, little is known about the underlying signaling pathways responsible for the colonization and growth of tumor cells in target organs. Since tyrosine kinase receptor activation is frequently associated with prostate cancer progression, we have investigated the role of a common signaling intermediary, activated Ras, in prostate cancer metastasis. Three effector pathways downstream of Ras, Raf/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase, and Ral guanine nucleotide exchange factors (RalGEFs), were assayed for their ability to promote the metastasis of a tumorigenic, nonmetastatic human prostate cancer cell line, DU145. Oncogenic Ras promoted the metastasis of DU145 to multiple organs, including bone and brain. Activation of the Raf/ERK pathway stimulated metastatic colonization of the brain, while activation of the RalGEF pathway led to bone metastases, the most common organ site for prostate cancer metastasis. In addition, loss of RalA in the metastatic PC3 cell line inhibited bone metastasis but did not affect subcutaneous tumor growth. Loss of Ral appeared to suppress expansive growth of prostate cancer cells in bone, whereas homing and initial colonization were less affected. These data extend our understanding of the functional roles of the Ral pathway and begin to identify signaling pathways relevant for organ-specific metastasis.

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Cerebral cavernous malformation 1 determines YAP/TAZ signaling dependent metastatic hallmarks of prostate cancer cells

10.1101/2020.04.23.057778 ◽

2020 ◽

Author(s):

Sangryoung Park ◽

Ho-Yong Lee ◽

Hansol Park ◽

Young Seok Ju ◽

Jayoung Kim ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Cancer Metastasis ◽

Cavernous Malformation ◽

Predictive Biomarker ◽

Cerebral Cavernous Malformation ◽

Binding Motif ◽

Prostate Cancer Cells ◽

Prostate Cancer Metastasis

AbstractEnhanced Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signaling is correlated with the extraprostatic extension of prostate cancer. However, the mechanism by which YAP/TAZ signaling becomes hyperactive and drives prostate cancer progression is currently unclear. In this study, we demonstrated that CCM1 induces the metastasis of multiple types of prostate cancer cells by regulating YAP/TAZ signaling. Mechanistically, CCM1, a gene mutated in cerebral cavernous malformation, suppresses DDX5, which regulates the PLK1-mediated suppression of YAP/TAZ signaling, indicating that CCM1 and DDX5 are novel upstream regulators of YAP/TAZ signaling. We also revealed that higher expression of CCM1, which is uniquely found in advanced prostate cancer, is inversely correlated with metastasis-free and overall survival in patients with prostate cancer. Our findings highlight the importance of CCM1-DDX5-PLK1-YAP/TAZ signaling in the metastasis of prostate cancer cells.Statement of SignificanceOur analysis of CCM1 expression and function represents a candidate predictive biomarker for prostate cancer metastasis and provides an evidence that abnormality of CCM1 can be pathogenic in prostate cancer. Importantly, CCM1 regulation of metastasis progression appears to a common molecular event in metastatic prostate cancer cells arising in disparate genetic backgrounds.

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Role of Exosomes in Prostate Cancer Metastasis

International Journal of Molecular Sciences ◽

10.3390/ijms22073528 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3528

Author(s):

Theresa Akoto ◽

Sharanjot Saini

Keyword(s):

Prostate Cancer ◽

Tumor Cells ◽

Extracellular Vesicles ◽

Cancer Progression ◽

Intercellular Communication ◽

Cancer Metastasis ◽

Disseminated Tumor Cells ◽

Bilayer Membrane ◽

Prostate Cancer Progression ◽

Prostate Cancer Metastasis

Prostate cancer remains a life-threatening disease among men worldwide. The majority of PCa-related mortality results from metastatic disease that is characterized by metastasis of prostate tumor cells to various distant organs, such as lung, liver, and bone. Bone metastasis is most common in prostate cancer with osteoblastic and osteolytic lesions. The precise mechanisms underlying PCa metastasis are still being delineated. Intercellular communication is a key feature underlying prostate cancer progression and metastasis. There exists local signaling between prostate cancer cells and cells within the primary tumor microenvironment (TME), in addition to long range signaling wherein tumor cells communicate with sites of future metastases to promote the formation of pre-metastatic niches (PMN) to augment the growth of disseminated tumor cells upon metastasis. Over the last decade, exosomes/ extracellular vesicles have been demonstrated to be involved in such signaling. Exosomes are nanosized extracellular vesicles (EVs), between 30 and 150 nm in thickness, that originate and are released from cells after multivesicular bodies (MVB) fuse with the plasma membrane. These vesicles consist of lipid bilayer membrane enclosing a cargo of biomolecules, including proteins, lipids, RNA, and DNA. Exosomes mediate intercellular communication by transferring their cargo to recipient cells to modulate target cellular functions. In this review, we discuss the contribution of exosomes/extracellular vesicles in prostate cancer progression, in pre-metastatic niche establishment, and in organ-specific metastases. In addition, we briefly discuss the clinical significance of exosomes as biomarkers and therapeutic agents.

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m6A Methylation Regulators Are Predictive Biomarkers for Tumour Metastasis in Prostate Cancer

10.21203/rs.3.rs-95052/v1 ◽

2020 ◽

Author(s):

Xiaobo Wu ◽

Qianwen Ge ◽

Chen Yang ◽

Yishuo Wu ◽

Mengbo Hu ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Cancer Metastasis ◽

Immune Cell ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Consensus Clustering ◽

Prostate Cancer Progression ◽

Prostate Cancer Metastasis ◽

Prostate Cancers

Abstract BackgroundProstate cancer is one of the most common cancers in men. Usually, most prostate cancers are localized in initial diagnoses and grow slowly. Patients with localized prostate cancers have a nearly 100% 5-year survival rate; however, the 5-year survival rate of metastatic or progressive prostate cancer is still dismal. N6-methyladenosine (m6A) is the most common post-transcriptional mRNA modification and is dynamically regulated by m6A regulators. A few studies have shown that the abnormal expression of m6A regulators is significantly associated with cancer progression and immune cell infiltration, but the roles of these regulators in prostate cancer remain unclear. MethodsHere, we comprehensively examined the patterns of 21 m6A regulators across 494 prostate cancers and systematically correlated m6A regulators with prostate cancer progression and immune cell infiltration. Consensus clustering was utilized for the subtype identification of m6A regulators for prostate cancers. Each subtype signature genes were obtained by the pairwise differentially expressed genes. Featured pathways of m6A subtypes were predicted consequently. The m6A score was constructed to predict the m6A activation. The association of m6A score with patients’ survival, metastasis and immune cell infiltration were also investigated. ResultsWe identified three distinct clusters in prostate cancer based on the expression profiles of 21 m6A regulators by consensus clustering. The differential expression and pathway analyses on the three clusters uncovered the m6A regulators involved in metabolic processes and immune responses in prostate cancer. Moreover, we established an m6A score to perceive the m6A regulator activation for prostate cancer. The m6A score is significantly associated with Gleason scores and metastasis in prostate cancer. The predictive capacity of m6A score on prostate cancer metastasis was also validated in another independent cohort. ConclusionOur study revealed the critical role of m6A regulators in prostate cancer progression and m6A score is promising predictive biomarker for prostate cancer metastasis.

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