Cholesterol level of lipid raft microdomains regulates apoptotic cell death in prostate cancer cells through EGFR‐mediated Akt and ERK signal transduction

Oh, Hyun-Joo; Lee, Eun Jin; Yoon, Sun Och; Chung, Byung Ha; Cho, Kang Su; Hong, Sung Joon

doi:10.1002/pros.20593

Cited by 90 publications

(60 citation statements)

References 41 publications

(45 reference statements)

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“…These data suggest that lipid rafts are key sites for CXCL12/CXCR4 transactivation of HER2 in prostate cancer cells. As a consequence of lipid raft disruption, EGFR downstream signaling pathways were inhibited in prostate cancer cells (47). Our data further show that cellular consequences of lipid raft disruption resulted in an inhibition of basal and CXCL12-mediated chemoinvasion of PC-3 cells (Fig.…”

Section: Discussionsupporting

confidence: 77%

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

Chinni

Yamamoto

Dong

et al. 2008

Molecular Cancer Research

118

102

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Chemokines and their receptors function in migration and homing of cells to target tissues. Recent evidence suggests that cancer cells use a chemokine receptor axis for metastasis formation at secondary sites. Previously, we showed that binding of the chemokine CXCL12 to its receptor CXCR4 mediated signaling events resulting in matrix metalloproteinase-9 expression in prostate cancer bone metastasis. A variety of methods, including lipid raft isolation, stable overexpression of CXCR4, cellular adhesion, invasion assays, and the severe combined immunodeficient -human bone tumor growth model were used. We found that (a) CXCR4 and HER2 coexist in lipid rafts of prostate cancer cells; (b) the CXCL12/CXCR4 axis results in transactivation of the HER2 receptor in lipid rafts of prostate cancer cells; (c) Src kinase mediates CXCL12/CXCR4 transactivation of HER2 in prostate cancer cells; (d) a pan-HER inhibitor desensitizes CXCR4-induced transactivation and subsequent matrix metalloproteinase-9 secretion and invasion; (e) lipid raft -disrupting agents inhibited raft-associated CXCL12/CXCR4 transactivation of the HER2 and cellular invasion; (f) overexpression of CXCR4 in prostate cancer cells leads to increased HER2 phosphorylation and migratory properties of prostate cancer cells; and (g) CXCR4 overexpression enhances bone tumor growth and osteolysis. These data suggest that lipid rafts on the cell membrane are the key site for CXCL12/CXCR4 -induced HER2 receptor transactivation. This transactivation contributes to enhanced invasive signals and metastatic growth in the bone microenvironment.

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Section: Discussionsupporting

confidence: 77%

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

Chinni

Yamamoto

Dong

et al. 2008

Molecular Cancer Research

118

102

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“…In this study, we showed that ␤2M mAb inhibited a large number of cell signaling networks, including MAPK, SREBP-1, AR, and PI3K/Akt. It is conceivable that these signaling networks are interconnected through lipid raft complexes (47,48). The inhibitory action exerted by ␤2M mAb could affect the lipid composition of the raft structures, hence altering domain interactions and how downstream cell signal networks can be assembled and interact in a coordinated manner (45,49).…”

Section: Discussionmentioning

confidence: 99%

Androgen Receptor Survival Signaling Is Blocked by Anti-β2-microglobulin Monoclonal Antibody via a MAPK/Lipogenic Pathway in Human Prostate Cancer Cells

Huang

Zhau

Chung

2010

Journal of Biological Chemistry

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A new cis-acting element, sterol regulatory element-binding protein-1 (SREBP-1) binding site, within the 5-flanking human androgen receptor (AR) promoter region and its binding transcription factor, SREBP-1, was identified to regulate AR transcription in AR-positive human prostate cancer cells. We further characterized the molecular mechanism by which a novel anti-␤2-microglobulin monoclonal antibody (␤2M mAb), shown to induce massive cell death in a number of human and mouse cancer cell lines, interrupted multiple cell signaling pathways in human prostate cancer cells. ␤2M mAb decreased AR expression through inactivation of MAPK and SREBP-1. By inactivation of MAPK, ␤2M mAb decreased prostate cancer cell proliferation and survival. By inhibition of SREBP-1, ␤2M mAb reduced fatty acid and lipid levels, an integral component of cell membrane, cell signaling mediators, and energy metabolism. These results provide for the first time a molecular link between the ␤2M intracellular signaling axis mediated by MAPK and SREBP-1 and involving lipid signaling, which collectively regulates AR expression and function. Antagonizing ␤2M by ␤2M mAb may be an effective therapeutic approach simultaneously targeting multiple downstream signaling pathways converging with MAPK, SREBP-1, and AR, important for controlling prostate cancer cell growth, survival, and progression. ␤2-Microglobulin (␤2M)3 is a co-receptor of a major histocompatibility complex class I antigen. ␤2M has been implicated in the regulation of the host immune mechanism and is essential for the recognition of foreign antigens by T-lymphocytes (1). Recent reports from our laboratory and others assigned additional biological functions to ␤2M as a diagnostic and prognostic indicator for multiple myeloma, prostate, and breast cancers (2-5); a growth factor and a signaling molecule (6, 7); a new androgen and androgen receptor (AR) target gene (8); and an attractive new therapeutic target for both liquid (9) and solid (10, 11) tumor malignancies. Blockade of ␤2M and its related signaling pathways by sequence-specific siRNA or antibody resulted in the inhibition of AR expression and activity and the induction of extensive prostate cancer cell death in vitro as well as prostate tumor regression in immune-compromised mice (7, 10). In addition, anti-␤2M monoclonal antibody (␤2M mAb) has been shown not to significantly affect the growth of normal cells, consistent with experimental observations where transgenic mice with a ␤2M deficit had normal organ function and life expectancy (9, 10, 12). Therefore, ␤2M and its signaling axis may offer an opportunity for improving the clinical targeting of prostate cancer.AR is a key growth and survival regulatory transcription factor for androgen target organs during normal development and neoplastic progression. Recognition of the importance of the AR signaling axis, particularly in castration-resistant prostate cancer, has prompted discoveries targeting androgen biosynthetic pathways using abiraterone as an agent for a Phase III trial...

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“…Important growth-signaling complexes for pathways such as TGFb, EGFR/MAPK/ERK, AKT, and the AR reside within cholesterol-rich microdomains referred to as lipid rafts whose signaling integrity can be modulated by changes in cellular cholesterol levels that affect membrane fluidity, transport, and protein complex assembly and stability Freeman et al, 2007;Montero et al, 2008). Elevated mitochondrial cholesterol associated with different cancers has also been demonstrated to impair the BAX-mediated apoptotic permeability pore associated with apoptosis and provide an apoptotic escape mechanism (Zhuang et al, 2005;Li et al, 2006Li et al, , 2008MartinezAbundis et al, 2007;Oh et al, 2007;Christenson et al, 2008).…”

Section: Fredericks Et Almentioning

confidence: 99%

“…However, there is also a separate recognition that elevated intracellular cholesterol in non-hormone-dependent tumor cells can contribute to progression based on numerous reports of interference with multiple pathways of growth signaling and apoptosis (Zhuang et al, 2005;Li et al, 2006;Swinnen et al, 2006;Adam et al, 2007;Freeman et al, 2007;Martinez-Abundis et al, 2007;Oh et al, 2007;Christenson et al, 2008;Patra, 2008). The link between intracellular cholesterol and tumor progression has been found in hepatocellular carcinoma, colon, breast, head and neck, and melanoma cancers, either with tumor specimens and/or studies in cancer cell lines (Schabath et al, 2006;Baruthio et al, 2008;Montero et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

Fredericks

McGarvey

Wang

et al. 2011

DNA and Cell Biology

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Convergent evidence implicates the TERE1 protein in human bladder tumor progression and lipid metabolism. Previously, reduced TERE1 expression was found in invasive urologic cancers and inhibited cell growth upon re-expression. A role in lipid metabolism was suggested by TERE1 binding to APOE, a cholesterol carrier, and to TBL2, a candidate protein in triglyceride disorders. Natural TERE1 mutations associate with Schnyder's corneal dystrophy, characterized by lipid accumulation. TERE1 catalyzes menaquinone synthesis, known to affect cholesterol homeostasis. To explore this relationship, we altered TERE1 and TBL2 dosage via ectopic expression and interfering RNA and measured cholesterol by Amplex red. Protein interactions of wild-type and mutant TERE1 with GST-APOE were evaluated by binding assays and molecular modeling. We conducted a bladder tumor microarray TERE1 expression analysis and assayed tumorigenicity of J82 cells ectopically expressing TERE1. TERE1 expression was reduced in a third of invasive specimens. Ectopic TERE1 expression in J82 bladder cancer cells dramatically inhibited nude mouse tumorigenesis. TERE1 and TBL2 proteins inversely modulated cellular cholesterol in HEK293 and bladder cancer cells from 20% to 50%. TERE1 point mutations affected APOE interactions, and resulted in cholesterol levels that differed from wild type. Elevated tumor cell cholesterol is known to affect apoptosis and growth signaling; thus, loss of TERE1 in invasive bladder cancer may represent a defect in menaquinone-mediated cholesterol homeostasis that contributes to progression.

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Cholesterol level of lipid raft microdomains regulates apoptotic cell death in prostate cancer cells through EGFR‐mediated Akt and ERK signal transduction

Abstract: Lipid raft cholesterol regulates apoptotic cell death in prostate cancer cells through EGFR-mediated Akt and ERK pathways.

Cited by 90 publications

References 41 publications

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

CXCL12/CXCR4 Transactivates HER2 in Lipid Rafts of Prostate Cancer Cells and Promotes Growth of Metastatic Deposits in Bone

Androgen Receptor Survival Signaling Is Blocked by Anti-β2-microglobulin Monoclonal Antibody via a MAPK/Lipogenic Pathway in Human Prostate Cancer Cells

The Bladder Tumor Suppressor Protein TERE1 (UBIAD1)Modulates Cell Cholesterol: Implications for Tumor Progression

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