The Renin–Angiotensin System Mediates EGF Receptor–Vitamin D Receptor Cross-Talk in Colitis-Associated Colon Cancer

Dougherty, Urszula; Mustafi, Reba; Sadiq, Farhana; Almoghrabi, Anas; Mustafi, Devkumar; Kreisheh, Maggi; Sundaramurthy, Sumana; Liu, Weicheng; Konda, Vani J.; Pekow, Joel; Khare, Sharad; Hart, John; Joseph, Loren; Wyrwicz, Alice M.; Li, Yan Chun; Bissonnette, Marc

doi:10.1158/1078-0432.ccr-14-0209

Cited by 39 publications

(29 citation statements)

References 60 publications

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“…RAS is mitogenic and angiogenic, and contributes to neoplastic growth in ovarian, prostate, lung, breast and pancreatic cancers (25). A number of RAS components, including renin, renin-receptor, ACE and AngII, are locally upregulated in tumors (26). In the present study, these molecules were significantly reduced by elemene treatment, suggesting that its antitumor effects may involve downregulation of the RAS signaling pathway.…”

Section: Discussionsupporting

confidence: 49%

Elemene inhibits osteosarcoma growth by suppressing the renin‑angiotensin system signaling pathway

et al. 2017

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Osteosarcoma remains the most prevalent primary malignant bone tumor in children and young adults globally. Therefore, novel and highly effective antitumor agents are urgently required. Elemene is a natural plant compound extracted from the medicinal Chinese herb, Rhizomazedoariae, which has been employed as an antitumor agent for the treatment of a number of tumors, including osteosarcoma. However, the mechanisms underlying its antitumor effect are currently unclear. The human osteosarcoma cell lines, MG‑63 and U2OS, were employed in the present study. MTT, migration, transwell invasion and terminal deoxynucleotidyltransferase‑mediated deoxy‑UTP‑fluorescein nick end‑labeling assays were performed to evaluate cell viability, migration, invasion and apoptosis, respectively. Western blotting and immunohistochemistry analyses were performed to measure the levels of renin‑angiotensin system (RAS) components. In order to evaluate the effect of elemene on tumor weight and volume, MG‑63 and U2OS cells were injected into mice. Treatment of osteosarcoma cell lines, MG‑63 and U2OS, with elemene led to the inhibition of cell viability, migration and invasion, as well as induction of cell apoptosis. In addition, elemene treatment downregulated the expression of a number of RAS components. The growth of osteosarcoma cell‑transplanted tumors in nude mice and angiotensin II expression were inhibited by elemene treatment. The results of the present study indicate that the antitumor effects of elemene may partly be due to downregulation of the RAS signaling pathway, and that RAS may be a putative pharmacological target for osteosarcoma therapy.

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Section: Discussionsupporting

confidence: 49%

Elemene inhibits osteosarcoma growth by suppressing the renin‑angiotensin system signaling pathway

et al. 2017

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“…Ang II stimulates their proliferation and induces production of various cytokines, such as TGF‐β, some of which have immunosuppressive functions. CAF, which are considered to be immunosuppressive cells in the cancer microenvironment, also express AT1R . Thus, we evaluated the effect of ARB treatment on CAF phenotypes in our mouse models.…”

Section: Resultsmentioning

confidence: 99%

“…CAF, which are considered to be immunosuppressive cells in the cancer microenvironment, 4 also express AT1R. 27 Thus, we evaluated the effect of ARB treatment on CAF phenotypes in our mouse models. For sorting of pure CAF, we used specially devised tumor-bearing mouse models in which MC38 cells labeled by a fluorescent protein, DsRed, were inoculated into CAG-EGFP transgenic mice that expressed EGFP ubiquitously.…”

Section: Arb Treatment Augmented the T-cell Stimulatory Activity Ofmentioning

confidence: 99%

Involvement of local renin‐angiotensin system in immunosuppression of tumor microenvironment

et al. 2017

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To improve current cancer immunotherapies, strategies to modulate various immunosuppressive cells including myeloid derived suppressor cells (MDSC) which were shown to be negative factors in immune‐checkpoint blockade therapy, need to be developed. In the present study, we evaluated the role of the local renin‐angiotensin system (RAS) in the tumor immune‐microenvironment using murine models bearing tumor cell lines in which RAS was not involved in their proliferation and angiogenetic ability. Giving angiotensin II receptor blockers (ARB) to C57BL/6 mice bearing murine colon cancer cell line MC38 resulted in significant enhancement of tumor antigen gp70 specific T cells. ARB administration did not change the numbers of CD11b+ myeloid cells in tumors, but significantly reduced their T‐cell inhibitory ability along with decreased production of various immunosuppressive factors including interleukin (IL)‐6, IL‐10, vascular endothelial growth factor (VEGF), and arginase by CD11b+ cells in tumors. ARB also decreased expression of immunosuppressive factors such as chemokine ligand 12 and nitric oxide synthase 2 in cancer‐associated fibroblasts (CAF). Last, combination of ARB and anti‐programmed death‐ligand 1 (PD‐L1) antibodies resulted in significant augmentation of anti‐tumor effects in a CD8+ T cell‐dependent way. These results showed that RAS is involved in the generation of an immunosuppressive tumor microenvironment caused by myeloid cells and fibroblasts, other than the previously shown proliferative and angiogenetic properties of cancer cells and macrophages, and that ARB can transform the immunosuppressive properties of MDSC and CAF and could be used in combination with PD‐1/PD‐L1 immune‐checkpoint blockade therapy.

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“…No study has focused on the effect of vitamin D3 supplementation on ACE expression. However, it has been observed that VDR knockout mice display an increased production of ACE mRNA [ 68 ]. Interestingly, this metalloprotease is involved in Alzheimer’s disease since human ACE increases degradation and cleavage of Aβ [ 69 – 72 ].…”

Section: Discussionmentioning

confidence: 99%

Vitamin D interacts with Esr1 and Igf1 to regulate molecular pathways relevant to Alzheimer’s disease

Landel

Millet

Baranger

et al. 2016

Mol Neurodegeneration

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BackgroundIncreasing evidence suggests a potential therapeutic benefit of vitamin D supplementation against Alzheimer’s disease (AD). Although studies have shown improvements in cognitive performance and decreases in markers of the pathology after chronic treatment, the mechanisms by which vitamin D acts on brain cells are multiple and remain to be thoroughly studied. We analyzed the molecular changes observed after 5 months of vitamin D3 supplementation in the brains of transgenic 5xFAD (Tg) mice, a recognized mouse model of AD, and their wild type (Wt) littermates. We first performed a kinematic behavioural examination at 4, 6 and 8 months of age (M4, M6 and M8) followed by a histologic assessment of AD markers. We then performed a comparative transcriptomic analysis of mRNA regulation in the neocortex and hippocampus of 9 months old (M9) female mice.ResultsTranscriptomic analysis of the hippocampus and neocortex of both Wt and Tg mice at M9, following 5 months of vitamin D3 treatment, reveals a large panel of dysregulated pathways related to i) immune and inflammatory response, ii) neurotransmitter activity, iii) endothelial and vascular processes and iv) hormonal alterations. The differentially expressed genes are not all direct targets of the vitamin D-VDR pathway and it appears that vitamin D action engages in the crosstalk with estrogen and insulin signaling. The misexpression of the large number of genes observed in this study translates into improved learning and memory performance and a decrease in amyloid plaques and astrogliosis in Tg animals.ConclusionsThis study underlies the multiplicity of action of this potent neurosteroid in an aging and AD-like brain. The classical and non-classical actions of vitamin D3 can act in an additive and possibly synergistic manner to induce neuroprotective activities in a context-specific way.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0087-2) contains supplementary material, which is available to authorized users.

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The Renin–Angiotensin System Mediates EGF Receptor–Vitamin D Receptor Cross-Talk in Colitis-Associated Colon Cancer

Cited by 39 publications

References 60 publications

Elemene inhibits osteosarcoma growth by suppressing the renin‑angiotensin system signaling pathway

Elemene inhibits osteosarcoma growth by suppressing the renin‑angiotensin system signaling pathway

Involvement of local renin‐angiotensin system in immunosuppression of tumor microenvironment

Vitamin D interacts with Esr1 and Igf1 to regulate molecular pathways relevant to Alzheimer’s disease

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