Transgenic expression of 15-lipoxygenase 2 (15-LOX2) in mouse prostate leads to hyperplasia and cell senescence

Suraneni, Mahipal; Schneider‐Broussard, Robin; Moore, John R.; Davis, Tammy; Maldonado, Carlos J.; Li, H; Newman, Robert A.; Kusewitt, Donna F.; Hu, Jian; Yang, Peiying; Tang, Dean G.

doi:10.1038/onc.2010.197

Cited by 39 publications

(67 citation statements)

References 51 publications

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“…Moreover, increased expression of 15-LOX2 in RCC, particularly in TAMs, was associated with elevated production of immunosuppressive and proinflammatory factors. Emerging evidence indicates that expression of 15-LOX2 in human macrophages could be upregulated by hypoxia (34), whereas transgenic overexpression of this enzyme in prostate tissue promotes hyperplasia (35). We speculate that in contrast to inflammation-resolving function of 15-LOX1, expression of 15-LOX2 in tumor microenvironment could be associated with cancer-related chronic inflammation and local immunosuppression.…”

Section: Discussionmentioning

confidence: 91%

Tumor-Associated Macrophages Mediate Immunosuppression in the Renal Cancer Microenvironment by Activating the 15-Lipoxygenase-2 Pathway

et al. 2011

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Renal cell carcinoma (RCC), the most common human kidney cancer, is frequently infiltrated with tumorassociated macrophages (TAM) that can promote malignant progression. Here, we show that TAMs isolated from human RCC produce substantial amounts of the proinflammatory chemokine CCL2 and immunosuppressive cytokine IL-10, in addition to enhanced eicosanoid production via an activated 15-lipoxygenase-2 (15-LOX2) pathway. TAMs isolated from RCC tumors had a high 15-LOX2 expression and secreted substantial amounts of 15(S)-hydroxyeicosatetraenoic acid, its major bioactive lipid product. Inhibition of lipoxygenase activity significantly reduced production of CCL2 and IL-10 by RCC TAMs. In addition, TAMs isolated from RCC were capable of inducing in T lymphocytes, the pivotal T regulatory cell transcription factor forkhead box P3 (FOXP3), and the inhibitory cytotoxic T-lymphocyte antigen 4 (CTLA-4) coreceptor. However, this TAMmediated induction of FOXP3 and CTLA-4 in T cells was independent of lipoxygenase and could not be reversed by inhibiting lipoxygenase activity. Collectively, our results show that TAMs, often present in RCCs, display enhanced 15-LOX2 activity that contributes to RCC-related inflammation, immunosuppression, and malignant progression. Furthermore, we show that TAMs mediate the development of immune tolerance through both 15-LOX2-dependent and 15-LOX2-independent pathways. We propose that manipulating LOX-dependent arachidonic acid metabolism in the tumor microenvironment could offer new strategies to block cancer-related inflammation and immune escape in patients with RCC. Cancer Res; 71(20); 6400-9. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 91%

Tumor-Associated Macrophages Mediate Immunosuppression in the Renal Cancer Microenvironment by Activating the 15-Lipoxygenase-2 Pathway

et al. 2011

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Section: Introductionmentioning

confidence: 99%

“…To determine whether 15-LOX2 truly possesses (prostate) tumor-suppressive functions in vivo, we have recently generated prostate-specific transgenic (Tg) mice using the ARR2Pb promoter 17 to drive the expression of full-length (fl) 15-LOX2 or, for comparison, 15-LOX2 splice variant b (15LOX2-svb) that lacks enzymatic activity 18 . Three 15-LOX2 (fl2, fl15, fl26) and 3 15LOX2-svb (svb9, svb10, svb15) Tg lines were established that exhibited various levels of transgene expression 18 . Subsequent characterizations and functional studies in fl26 and svb9 lines revealed 2 surprising findings: macroscopically, the fl26, and, in particular, the svb9 Tg prostates, were larger than the age-matched wild-type (WT) prostates; and microscopically, the fl26 prostates, and, less obviously, svb9 prostates, showed hyperplasia, which did not progress to PIN (prostate intraepithelial neoplasia) or adenocarcinoma 18 .…”

Section: Introductionmentioning

confidence: 99%

Tumor-suppressive functions of 15-Lipoxygenase-2 and RB1CC1 in prostate cancer

Suraneni¹,

Moore²,

Zhang³

et al. 2014

Cell Cycle

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15-Lipoxygenase-2 (15-LOX2) is a human-specific lipid-peroxidizing enzyme most prominently expressed in epithelial cells of normal human prostate but downregulated or completely lost in > 70% of prostate cancer (PCa) cases. Transgenic expression of 15-LOX2 in the mouse prostate surprisingly causes hyperplasia. Here we first provide evidence that 15-LOX2-induced prostatic hyperplasia does not progress to PCa even in p53+/− or p53−/− background. More important, by generating 15-LOX2; Hi-Myc double transgenic (dTg) mice, we show that 15-LOX2 expression inhibits Myc-induced PCa development, such that in the 3-month- and 6-month-old dTg mice, there is a significant reduction in prostate intraneoplasia (PIN) and PCa prevalent in age-matched Hi-Myc prostates. The dTg prostates show increased cell senescence and expression of several senescence-associated molecules, including p27, phosphorylated Rb, and Rb1cc1. We further show that in HPCa, 15-LOX2 and c-Myc manifest reciprocal protein expression patterns. Moreover, RB1CC1 accumulates in senescing normal human prostate (NHP) cells, and in both NHP and RWPE-1 cells, the 15-LOX2 metabolic products 15(S)-HPETE and 15(S)-HETE induce RB1CC1. We finally show that unlike 15-LOX2, RB1CC1 is not lost but rather frequently overexpressed in PCa samples. RB1CC1 knockdown in PC3 cells enhances clonal growth in vitro and tumor growth in vivo. Together, our present studies provide evidence for tumor-suppressive functions for both 15-LOX2 and RB1CC1.

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“…This suggests that following severe airway injury, when the blood supply may be interrupted and glucose supply is low, ALDH hi ABSCs may utilize AA in the local environment to facilitate proliferation for repair. Interestingly, the overexpression of lipoxygenase-15 in transgenic mice resulted in hyperplasia of prostate basal cells [41]. Further, lipoxygenases-12e and 15 have been linked to epithelial proliferation in corneal repair after injury [42].…”

Section: Discussionmentioning

confidence: 99%

Aldehyde Dehydrogenase Activity Enriches for Proximal Airway Basal Stem Cells and Promotes Their Proliferation

Hegab

Ha²,

Bisht³

et al. 2014

Stem Cells and Development

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Both basal and submucosal gland (SMG) duct stem cells of the airway epithelium are capable of sphere formation in the in vitro sphere assay, although the efficiency at which this occurs is very low. We sought to improve this efficiency of sphere formation by identifying subpopulations of airway basal stem cells (ABSC) and SMG duct cells based on their aldehyde dehydrogenase (ALDH) activity. ALDH hi ABSCs and SMG duct cells were highly enriched for the population of cells that could make spheres, while the co-culture of ALDH hi differentiated cells with the ALDH hi ABSCs increased their sphere-forming efficiency. Specific ALDH agonists and antagonists were used to show that airway specific ALDH isozymes are important for ABSC proliferation. Pathway analysis of gene expression profiling of ALDH hi and ALDH lo ABSCs revealed a significant upregulation of the arachidonic acid (AA) metabolism pathway in ALDH hi ABSCs. We confirmed the importance of this pathway in the metabolism of proliferating ALDH hi ABSCs using bioenergetics studies as well as agonists and antagonists of the AA pathway. These studies could lead to the development of novel strategies for altering ABSC proliferation in the airway epithelium.

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Transgenic expression of 15-lipoxygenase 2 (15-LOX2) in mouse prostate leads to hyperplasia and cell senescence

Cited by 39 publications

References 51 publications

Tumor-Associated Macrophages Mediate Immunosuppression in the Renal Cancer Microenvironment by Activating the 15-Lipoxygenase-2 Pathway

Tumor-Associated Macrophages Mediate Immunosuppression in the Renal Cancer Microenvironment by Activating the 15-Lipoxygenase-2 Pathway

Tumor-suppressive functions of 15-Lipoxygenase-2 and RB1CC1 in prostate cancer

Aldehyde Dehydrogenase Activity Enriches for Proximal Airway Basal Stem Cells and Promotes Their Proliferation

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