scholarly journals A Comprehensive Analysis of FUT8 Overexpressing Prostate Cancer Cells Reveals the Role of EGFR in Castration Resistance

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 468 ◽  
Author(s):  
Naseruddin Höti ◽  
Tung-Shing Lih ◽  
Jianbo Pan ◽  
Yangying Zhou ◽  
Ganglong Yang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Surface ◽  
Cancer Cells ◽  
Growth Factor Receptor ◽  
Androgen Deprivation ◽  
Cell Surface Receptor ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Prostate Cancer Cells

The emergence of castration-resistance is one of the major challenges in the management of patients with advanced prostate cancer. Although the spectrum of systemic therapies that are available for use alongside androgen deprivation for treatment of castration-resistant prostate cancer (CRPC) is expanding, none of these regimens are curative. Therefore, it is imperative to apply systems approaches to identify and understand the mechanisms that contribute to the development of CRPC. Using comprehensive proteomic approaches, we show that a glycosylation-related enzyme, alpha (1,6) fucosyltransferase (FUT8), which is upregulated in CRPC, might be responsible for resistance to androgen deprivation. Mechanistically, we demonstrated that overexpression of FUT8 resulted in upregulation of the cell surface epidermal growth factor receptor (EGFR) and corresponding downstream signaling, leading to increased cell survival in androgen-depleted conditions. We studied the coregulatory mechanisms of EGFR and FUT8 expression in CRPC xenograft models and found that castration induced FUT8 overexpression associated with increased expression of EGFR. Taken together, our findings suggest a crucial role played by FUT8 as a mediator in switching prostate cancer cells from nuclear receptor signaling (androgen receptor) to the cell surface receptor (EGFR) mechanisms in escaping castration-induced cell death. These findings have clinical implication in understanding the role of FUT8 as a master regulator of cell surface receptors in cancer-resistant phenotypes.

scholarly journals The Hippo Pathway Effector YAP Regulates Motility, Invasion, and Castration-Resistant Growth of Prostate Cancer Cells

2015 ◽  
Vol 35 (8) ◽  
pp. 1350-1362 ◽  
Author(s):  
Lin Zhang ◽  
Shuping Yang ◽  
Xingcheng Chen ◽  
Seth Stauffer ◽  
Fang Yu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Ectopic Expression ◽  
Migration And Invasion ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Lncap Cells ◽  
Prostate Cancer Cells ◽  
Prostate Tumors ◽  
Castration Resistant

Yes-associated protein (YAP) is an effector of the Hippo tumor suppressor pathway. The functional significance of YAP in prostate cancer has remained elusive. In this study, we first show that enhanced expression of YAP is able to transform immortalized prostate epithelial cells and promote migration and invasion in both immortalized and cancerous prostate cells. We found that YAP mRNA was upregulated in androgen-insensitive prostate cancer cells (LNCaP-C81 and LNCaP-C4-2 cells) compared to the level in androgen-sensitive LNCaP cells. Importantly, ectopic expression of YAP activated androgen receptor signaling and was sufficient to promote LNCaP cells from an androgen-sensitive state to an androgen-insensitive statein vitro, and YAP conferred castration resistancein vivo. Accordingly, YAP knockdown greatly reduced the rates of migration and invasion of LNCaP-C4-2 cells and under androgen deprivation conditions largely blocked cell division in LNCaP-C4-2 cells. Mechanistically, we found that extracellular signal-regulated kinase–ribosomal s6 kinase signaling was downstream of YAP for cell survival, migration, and invasion in androgen-insensitive cells. Finally, immunohistochemistry showed significant upregulation and hyperactivation of YAP in castration-resistant prostate tumors compared to their levels in hormone-responsive prostate tumors. Together, our results identify YAP to be a novel regulator in prostate cancer cell motility, invasion, and castration-resistant growth and as a potential therapeutic target for metastatic castration-resistant prostate cancer (CRPC).

scholarly journals Androgens and androgen receptor signaling in prostate tumorigenesis

2014 ◽  
Vol 54 (1) ◽  
pp. R15-R29 ◽  
Author(s):  
Ye Zhou ◽  
Eric C Bolton ◽  
Jeremy O Jones
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Cancer Growth ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Prostate Tumorigenesis ◽  
Prostate Development ◽  
Cancer Initiation

Androgens and androgen receptor (AR) signaling are necessary for prostate development and homeostasis. AR signaling also drives the growth of nearly all prostate cancer cells. The role of androgens and AR signaling has been well characterized in metastatic prostate cancer, where it has been shown that prostate cancer cells are exquisitely adept at maintaining functional AR signaling to drive cancer growth. As androgens and AR signaling are so intimately involved in prostate development and the proliferation of advanced prostate cancer, it stands to reason that androgens and AR are also involved in prostate cancer initiation and the early stages of cancer growth, yet little is known of this process. In this review, we summarize the current state of knowledge concerning the role of androgens and AR signaling in prostate tissue, from development to metastatic, castration-resistant prostate cancer, and use that information to suggest potential roles for androgens and AR in prostate cancer initiation.

scholarly journals The Role of S100A4 for Bone Metastasis in Prostate Cancer Cells

2020 ◽  
Author(s):  
Bongjun Kim ◽  
Haemin Kim ◽  
Suhan Jung ◽  
Jun-Oh Kwon ◽  
Min-Kyong Song ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Cell Surface Receptor ◽  
Prostate Cancer Cells ◽  
S100a4 Protein ◽  
Knock Down ◽  
Pc3 Cells

Abstract Background: Prostate cancers frequently metastasize to bone, where the best microenvironment for distant colonization is provided. Since osteotropic metastasis of prostate cancer is a critical determinant of patients’ survival, searches for preventive measures are ongoing in the field. Therefore, it is important to dissect the mechanisms of each step of bone metastasis, including the epithelial-mesenchymal transition (EMT) and cross-talk between metastatic niches and cancer cells.Methods: In this study, we established a highly bone-metastatic subline of human prostate cancer cells by selecting bone-homing population of PC3 cells after cardiac injection of eight-week-old male BALB/c-nude mice. Then we assessed the proliferation, EMT, and migration properties of the subline (mtPC3) cells in comparison with the parental PC3 cells. To investigate the role of S100A4, we performed gene knock-down by lentiviral transduction, or treated cells with recombinant S100A4 protein or a S100A4-neutralizing antibody. The effect of cancer cells on osteoclastogenesis was evaluated after treatment of pre-osteoclasts with conditioned medium (CM) from cancer cells.Results: The mtPC3 cells secreted a markedly high level of S100A4 protein and showed elevated cell proliferation and mesenchymal properties. The increased proliferation and EMT of mtPC3 cells was inhibited by S100A4 knock-down, but was not affected by exogenous S100A4. Furthermore, S100A4 released from mtPC3 cells stimulated osteoclast development via the cell surface receptor RAGE. Down-regulation or neutralization of S100A4 in the CM of mtPC3 cells attenuated cancer-induced osteoclastogenesis. Conclusion: Altogether, our results suggest that intracellular S100A4 promotes cell proliferation and EMT in tumor cells, and that secreted S100A4 activates osteoclastogenesis, contributing to osteolytic bone metastasis. Thus, S100A4 upregulation in cancer cells highly metastatic to bone might be a key element in regulating bone metastasis.

scholarly journals The role of S100A4 for bone metastasis in prostate cancer cells

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Bongjun Kim ◽  
Suhan Jung ◽  
Haemin Kim ◽  
Jun-Oh Kwon ◽  
Min-Kyoung Song ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Bone Metastasis ◽  
Cancer Cells ◽  
Cell Surface Receptor ◽  
Prostate Cancer Cells ◽  
S100a4 Protein ◽  
Knock Down ◽  
Pc3 Cells

Abstract Background Prostate cancers frequently metastasize to bone, where the best microenvironment for distant colonization is provided. Since osteotropic metastasis of prostate cancer is a critical determinant of patients’ survival, searches for preventive measures are ongoing in the field. Therefore, it is important to dissect the mechanisms of each step of bone metastasis, including the epithelial-mesenchymal transition (EMT) and cross-talk between metastatic niches and cancer cells. Methods In this study, we established a highly bone-metastatic subline of human prostate cancer cells by selecting bone-homing population of PC3 cells after cardiac injection of eight-week-old male BALB/c-nude mice. Then we assessed the proliferation, EMT characteristics, and migration properties of the subline (mtPC3) cells in comparison with the parental PC3 cells. To investigate the role of S100A4, we performed gene knock-down by lentiviral transduction, or treated cells with recombinant S100A4 protein or a S100A4-neutralizing antibody. The effect of cancer cells on osteoclastogenesis was evaluated after treatment of pre-osteoclasts with conditioned medium (CM) from cancer cells. Results The mtPC3 cells secreted a markedly high level of S100A4 protein and showed elevated cell proliferation and mesenchymal properties. The increased proliferation and EMT traits of mtPC3 cells was inhibited by S100A4 knock-down, but was not affected by exogenous S100A4. Furthermore, S100A4 released from mtPC3 cells stimulated osteoclast development via the cell surface receptor RAGE. Down-regulation or neutralization of S100A4 in the CM of mtPC3 cells attenuated cancer-induced osteoclastogenesis. Conclusion Altogether, our results suggest that intracellular S100A4 promotes cell proliferation and EMT characteristics in tumor cells, and that secreted S100A4 activates osteoclastogenesis, contributing to osteolytic bone metastasis. Thus, S100A4 upregulation in cancer cells highly metastatic to bone might be a key element in regulating bone metastasis.

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