Activation of Androgen Receptor, Lipogenesis, and Oxidative Stress Converged by SREBP-1 Is Responsible for Regulating Growth and Progression of Prostate Cancer Cells

Huang, Wen-Chin; Li, Xiangyan; Liu, Jian; Lin, Jen-Tai; Chung, Leland W.K.

doi:10.1158/1541-7786.mcr-11-0206

Cited by 197 publications

(191 citation statements)

References 46 publications

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“…Furthermore, Huang et al, (2011) reported that overexpression of SREBP-1 increased ROS content in prostate cancer cells [37]. These findings further support our results.…”

Section: Accepted Manuscriptsupporting

confidence: 89%

SREBP-1c overactivates ROS-mediated hepatic NF-κB inflammatory pathway in dairy cows with fatty liver

Huang

et al. 2015

Cellular Signalling

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“…Furthermore, Huang et al, (2011) reported that overexpression of SREBP-1 increased ROS content in prostate cancer cells [37]. These findings further support our results.…”

Section: Accepted Manuscriptsupporting

confidence: 89%

SREBP-1c overactivates ROS-mediated hepatic NF-κB inflammatory pathway in dairy cows with fatty liver

Huang

et al. 2015

Cellular Signalling

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“…Furthermore, we believe that the combined effect of both the DHT inhibition and the activation of AMPK caused a reduction in the expression of FASN in the group treated with a combination of dutasteride and metformin. This effect may be facilitated by the reduced expression in SREBP-1, which has recently been shown to regulate expression of AR [24]. This recent study by Huang et al showed that by genetically overexpressing or knocking down SREBP-1 in LNCaP cells resulted in a corresponding increase or decrease in AR expression [24].…”

Section: Discussionmentioning

confidence: 98%

“…This effect may be facilitated by the reduced expression in SREBP-1, which has recently been shown to regulate expression of AR [24]. This recent study by Huang et al showed that by genetically overexpressing or knocking down SREBP-1 in LNCaP cells resulted in a corresponding increase or decrease in AR expression [24]. Our data confirms the above reported findings where the greatest reduction in AR and PSA expression was seen with a combination group of dutasteride and metformin, with a corresponding reduction of SREBP-1.…”

Section: Discussionmentioning

confidence: 99%

Dutasteride and Metformin Reduce the Growth of LNCaP Cells and Alter the SREBP-1 Pathway

Besla

Venier²,

Colquhoun³

et al. 2013

TOPCANJ

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Prostate cancer (PCa) is the second most prevalent cancer in men after lung cancer. Prostate cancer development and progression is associated with the dysregulation of a number of molecular pathways; hence, therapeutic strategies targeting such pathways bring great promise. Recently we have shown that metformin, the anti-diabetic drug, can inhibit tumor progression when combined with dutasteride, a 5-alpha-reductase inhibitor (5ARI). Interestingly, both metformin and dutasteride have been reported to alter the Sterol Regulatory Element Binding Proteins (SREBP) Fatty Acid Synthase (FASN) pathway. The SREBP pathway is involved with lipid and energy homeostasis. In our present study, we investigated if dutasteride in combination with metformin can reduce the proliferation of LNCaP PCa cells, and whether this is mediated through the SREBP-1/FASN pathway. Human PCa cells were treated with either dutasteride (0-100 µM) or metformin (0-50 mM) alone or in combination. The treated cells were then incubated for up to 24 hours, and proliferation assessed using the MTS 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. Western blot analysis was performed on cell lysates to assess alterations in key signaling molecules including cleaved SREBP-1, FASN, AR, PSA, pAMPK and apoptotic markers. Results revealed that there was a significant (p<0.05) decrease in cellular proliferation of LNCaP cells treated with a combination of metformin and dutasteride, this effect being greater than either treatment alone. Treating LNCaP cells with both metformin and dutasteride reduced the expression of FASN, cleaved SREBP-1 and pro-caspase-3 with expression of cleaved PARP; suggesting a possible interaction between FASN and apoptosis. All treatments resulted in reductions in AR, PSA and an upregulation of pAMPK, with the highest expression seen in combination treatment. We report for the first time that metformin and dutasteride in combination can reduce the proliferation of androgen-sensitive cell line through the activation of p-AMPK, and SREBP-1/FASN pathway and highlight the importance of targeting the SREBP-1 pathway, for improving future therapeutic strategies for prostate cancer.

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“…In contrast, significant levels of NOX5 have been reported in PC-3 human prostate cancer cells. Detection of NOX5 in PC-3 cells coupled with the observation that NOX5 expression is upregulated by sterol regulatory element-binding protein-1 both in vitro and in vivo in the context of prostate cancer progression, does implicate a proliferative role for NOX5 in prostate cancer (54). There have been two other detailed studies of NOX5 in the context of tumor biology; in 2005, the expression of NOX5 in hairy cell leukemia was reported to regulate constitutive phosphorylation signals mediating proliferation, and in 2006, acidinduced NOX5-S expression was reported to contribute to increased cell proliferation and decreased apoptosis in Barrett's esophageal adenocarcinoma cells (38,61).…”

mentioning

confidence: 98%

NADPH Oxidases: A Perspective on Reactive Oxygen Species Production in Tumor Biology

Meitzler

Antony

et al. 2014

Antioxidants & Redox Signaling

169

143

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Significance: Reactive oxygen species (ROS) promote genomic instability, altered signal transduction, and an environment that can sustain tumor formation and growth. The NOX family of NADPH oxidases, membranebound epithelial superoxide and hydrogen peroxide producers, plays a critical role in the maintenance of immune function, cell growth, and apoptosis. The impact of NOX enzymes in carcinogenesis is currently being defined and may directly link chronic inflammation and NOX ROS-mediated tumor formation. Recent Advances: Increased interest in the function of NOX enzymes in tumor biology has spurred a surge of investigative effort to understand the variability of NOX expression levels in tumors and the effect of NOX activity on tumor cell proliferation. These initial efforts have demonstrated a wide variance in NOX distribution and expression levels across numerous cancers as well as in common tumor cell lines, suggesting that much remains to be discovered about the unique role of NOX-related ROS production within each system. Progression from in vitro cell line studies toward in vivo tumor tissue screening and xenograft models has begun to provide evidence supporting the importance of NOX expression in carcinogenesis. Critical Issues: A lack of universally available, isoform-specific antibodies and animal tumor models of inducible knockout or over-expression of NOX isoforms has hindered progress toward the completion of in vivo studies. Future Directions: In vivo validation experiments and the use of large, existing gene expression data sets should help define the best model systems for studying the NOX homologues in the context of cancer. Antioxid. Redox Signal. 20, 2873Signal. 20, -2889

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Activation of Androgen Receptor, Lipogenesis, and Oxidative Stress Converged by SREBP-1 Is Responsible for Regulating Growth and Progression of Prostate Cancer Cells

Cited by 197 publications

References 46 publications

SREBP-1c overactivates ROS-mediated hepatic NF-κB inflammatory pathway in dairy cows with fatty liver

SREBP-1c overactivates ROS-mediated hepatic NF-κB inflammatory pathway in dairy cows with fatty liver

Dutasteride and Metformin Reduce the Growth of LNCaP Cells and Alter the SREBP-1 Pathway

NADPH Oxidases: A Perspective on Reactive Oxygen Species Production in Tumor Biology

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