Cyclin D1 and cyclin D3 show divergent responses to distinct mitogenic stimulation

Anderson, Alexandra; Child, Emma S.; Prasad, Aarathi; Elphick, Lucy M.; Mann, David J.

doi:10.1002/jcp.22207

Cited by 7 publications

(4 citation statements)

References 41 publications

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“…Unlike individual p38 MAPK or ERK MAPK inhibitors, sorafenib treatment also decreased cyclin D3 expression. These findings suggest that sorafenib targets MAPK independent pathways essential for cell cycle progression and proliferation, and are consistent with previously published reports showing that cyclin D1 and cyclin D3 are differentially regulated [32]. Therapies targeting both cyclins may be most effective at inhibiting cell growth and successfully inducing tumor regression.…”

Section: Discussionsupporting

confidence: 91%

Sorafenib combined with HER-2 targeted vaccination can promote effective T cell immunity in vivo

Sunay

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Leatherman

et al. 2017

International Immunopharmacology

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The tumor microenvironment (TME) is established and maintained through complex interactions between tumor cells and host stromal elements. Therefore, therapies that target multiple cellular components of the tumor may be most effective. Sorafenib, a multi-kinase inhibitor, alters signaling pathways in both tumor cells and host stromal cells. Thus, we explored the potential immune-modulating effects of sorafenib in a murine HER-2-(neu) overexpressing breast tumor model alone and in combination with a HER-2 targeted granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting vaccine (3T3neuGM). In vitro, sorafenib inhibited the growth of HER-2 overexpressing NT2.5 tumor cells, inducing apoptosis. Sorafenib also interfered with ERK MAPK, p38 MAPK, and STAT3 signaling, as well as cyclin D expression, but did not affect HER-2 or AKT signaling. In vivo, single agent sorafenib disrupted the tumor-associated vasculature and induced tumor cell apoptosis, effectively inducing the regression of established NT2.5 tumors in immune competent FVB/N mice. Immune depletion studies demonstrated that both CD4+ and CD8+ T cells were required for tumor regression. Sorafenib treatment did not impact the rate of tumor clearance induced by vaccination with 3T3neuGM in tumor-bearing FVB/N mice relative to either sorafenib treatment or vaccination alone. In vivo studies further demonstrated that sorafenib enhanced the accumulation of both CD4+ and CD8+ T cells into the TME of vaccinated mice. Together, these findings suggest that GM-CSF-secreting cellular immunotherapy may be integrated with sorafenib without impairing vaccine-based immune responses.

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Section: Discussionsupporting

confidence: 91%

Sorafenib combined with HER-2 targeted vaccination can promote effective T cell immunity in vivo

Sunay

Foote

Leatherman

et al. 2017

International Immunopharmacology

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“…Our in vitro data demonstrate that NM922 reduced the conversion of normal fibroblasts to myofibroblasts in the presence of TGF-␤ by inhibiting the activation of FAK-Akt-p70S6K (18,37) and mTOR/STAT3/ 4E-BP1 (4, 5, 21) profibrotic pathways. Meanwhile, NM922 treatment reduced the levels of the cell cycle regulator protein cyclin D3, which is a downstream effector of mTOR, corroborating the inhibitory effects of NM922 on the STAT3/4E-BP1 pathway (2). We also demonstrated that daily administration of NM922 initiated at 6 wk after TAC attenuated maladaptive LV remodeling and preserved LV function compared with vehicle.…”

Section: Discussionsupporting

confidence: 72%

A novel fibroblast activation inhibitor attenuates left ventricular remodeling and preserves cardiac function in heart failure

Bradley

Spaletra

et al. 2018

American Journal of Physiology-Heart and Circulatory Physiology

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Cardiac fibroblasts are critical mediators of fibrotic remodeling in the failing heart and transform into myofibroblasts in the presence of profibrotic factors such as transforming growth factor-β. Myocardial fibrosis worsens cardiac function, accelerating the progression to decompensated heart failure (HF). We investigated the effects of a novel inhibitor (NM922; NovoMedix, San Diego, CA) of the conversion of normal fibroblasts to the myofibroblast phenotype in the setting of pressure overload-induced HF. NM922 inhibited fibroblast-to-myofibroblast transformation in vitro via a reduction of activation of the focal adhesion kinase-Akt-p70S6 kinase and STAT3/4E-binding protein 1 pathways as well as via induction of cyclooxygenase-2. NM922 preserved left ventricular ejection fraction ( P < 0.05 vs. vehicle) and significantly attenuated transverse aortic constriction-induced LV dilation and hypertrophy ( P < 0.05 compared with vehicle). NM922 significantly ( P < 0.05) inhibited fibroblast activation, as evidenced by reduced myofibroblast counts per square millimeter of tissue area. Picrosirius red staining demonstrated that NM922 reduced ( P < 0.05) interstitial fibrosis compared with mice that received vehicle. Similarly, NM922 hearts had lower mRNA levels ( P < 0.05) of collagen types I and III, lysyl oxidase, and TNF-α at 16 wk after transverse aortic constriction. Treatment with NM922 after the onset of cardiac hypertrophy and HF resulted in attenuated myocardial collagen formation and adverse remodeling with preservation of left ventricular ejection fraction. Future studies are aimed at further elucidation of the molecular and cellular mechanisms by which this novel antifibrotic agent protects the failing heart. NEW & NOTEWORTHY Our data demonstrated that a novel antifibrotic agent, NM922, blocks the activation of fibroblasts, reduces the formation of cardiac fibrosis, and preserves cardiac function in a murine model of heart failure with reduced ejection fraction.

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“…Cyclin D1 and cyclin D3 have differing mechanisms of regulation and exert distinct functional effects [15]. Findings that will be presented here indicate that high cyclin D3 expression can induce erlotinib resistance in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 76%

High cyclin D3 expression confers erlotinib resistance in aerodigestive tract cancer

et al. 2011

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Cyclin D1 and cyclin D3 show divergent responses to distinct mitogenic stimulation

Cited by 7 publications

References 41 publications

Sorafenib combined with HER-2 targeted vaccination can promote effective T cell immunity in vivo

Sorafenib combined with HER-2 targeted vaccination can promote effective T cell immunity in vivo

A novel fibroblast activation inhibitor attenuates left ventricular remodeling and preserves cardiac function in heart failure

High cyclin D3 expression confers erlotinib resistance in aerodigestive tract cancer

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