scholarly journals α1-Adrenergic Receptor Antagonists: Novel Therapy for Pituitary Adenomas

2005 ◽  
Vol 19 (12) ◽  
pp. 3085-3096 ◽  
Author(s):  
Manory A. Fernando ◽  
Anthony P. Heaney
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Pituitary Tumor ◽  
Adrenergic Receptor ◽  
Pituitary Tumors ◽  
Nuclear Factor Κb ◽  
Nuclear Factor

Abstract Pituitary tumors are common and cause considerable morbidity due to local invasion and altered hormone secretion. Doxazosin (dox), a selective α1-adrenergic receptor antagonist, used to treat hypertension, also inhibits prostate cancer cell proliferation. We examined the effects of dox on murine and human pituitary tumor cell proliferation in vitro and in vivo. dox treatment inhibited proliferation of murine pituitary tumor cells, induced G0-G1 cell cycle arrest, and reduced phosphorylated retinoblastoma levels. In addition, increased annexin-fluorescein isothiocyanate immunoreactivity and cleaved caspase-3 levels, in keeping with dox-mediated apoptosis, were observed in the human and murine pituitary tumor cells, and dox administration to mice, harboring corticotroph tumors, decreased tumor growth and reduced plasma ACTH levels. dox-mediated antiproliferative and proapoptotic actions were not confined to α-adrenergic receptor-expressing pituitary tumor cells and were unaffected by cotreatment with the α-adrenergic receptor blocker, phenoxybenzamine. dox treatment led to reduced phosphorylated inhibitory κB (IκB)-α expression, and nuclear factor-κB transcription and decreased basal and TNFα-induced proopiomelanocortin transcriptional activation. These results demonstrate that the selective α1-adrenergic receptor antagonist dox inhibits pituitary tumor cell growth in vitro and in vivo by mechanisms that are in part independent of its α-adrenergic receptor-blocking actions and involve down-regulation of nuclear factor-κB signaling. dox is proposed as a possible novel medical therapy for pituitary tumors.

scholarly journals Tumor quiescence: elevating SOX2 in diverse tumor cell types downregulates a broad spectrum of the cell cycle machinery and inhibits tumor growth

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Ethan P. Metz ◽  
Erin L. Wuebben ◽  
Phillip J. Wilder ◽  
Jesse L. Cox ◽  
Kaustubh Datta ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cell Cycle Machinery

Abstract Background Quiescent tumor cells pose a major clinical challenge due to their ability to resist conventional chemotherapies and to drive tumor recurrence. Understanding the molecular mechanisms that promote quiescence of tumor cells could help identify therapies to eliminate these cells. Significantly, recent studies have determined that the function of SOX2 in cancer cells is highly dose dependent. Specifically, SOX2 levels in tumor cells are optimized to promote tumor growth: knocking down or elevating SOX2 inhibits proliferation. Furthermore, recent studies have shown that quiescent tumor cells express higher levels of SOX2 compared to adjacent proliferating cells. Currently, the mechanisms through which elevated levels of SOX2 restrict tumor cell proliferation have not been characterized. Methods To understand how elevated levels of SOX2 restrict the proliferation of tumor cells, we engineered diverse types of tumor cells for inducible overexpression of SOX2. Using these cells, we examined the effects of elevating SOX2 on their proliferation, both in vitro and in vivo. In addition, we examined how elevating SOX2 influences their expression of cyclins, cyclin-dependent kinases (CDKs), and p27Kip1. Results Elevating SOX2 in diverse tumor cell types led to growth inhibition in vitro. Significantly, elevating SOX2 in vivo in pancreatic ductal adenocarcinoma, medulloblastoma, and prostate cancer cells induced a reversible state of tumor growth arrest. In all three tumor types, elevation of SOX2 in vivo quickly halted tumor growth. Remarkably, tumor growth resumed rapidly when SOX2 returned to endogenous levels. We also determined that elevation of SOX2 in six tumor cell lines decreased the levels of cyclins and CDKs that control each phase of the cell cycle, while upregulating p27Kip1. Conclusions Our findings indicate that elevating SOX2 above endogenous levels in a diverse set of tumor cell types leads to growth inhibition both in vitro and in vivo. Moreover, our findings indicate that SOX2 can function as a master regulator by controlling the expression of a broad spectrum of cell cycle machinery. Importantly, our SOX2-inducible tumor studies provide a novel model system for investigating the molecular mechanisms by which elevated levels of SOX2 restrict cell proliferation and tumor growth.

scholarly journals Suppressive effects of dehydroepiandrosterone and the nuclear factor-κB inhibitor parthenolide on corticotroph tumor cell growth and function in vitro and in vivo

2006 ◽  
Vol 188 (2) ◽  
pp. 321-331 ◽  
Author(s):  
T Taguchi ◽  
T Takao ◽  
Y Iwasaki ◽  
M Nishiyama ◽  
K Asaba ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Survivin Expression ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Aging Effects ◽  
And Function

Dehydroepiandrosterone (DHEA) is believed to have an anti-tumor effect, as well as anti-inflammatory, antioxidant, and anti-aging effects. To clarify the possible inhibitory action of DHEA on pituitary tumor cells, we tested the effects of DHEA, alone or in combination with the nuclear factor-κB (NF-κB) inhibitor parthenolide (PRT), on AtT20 corticotroph cell growth and function both in vitro and in vivo. We found that, in vitro, DHEA and PRT had potent inhibitory effects on pro-opiomelanocortin and NF-κB-dependent gene expression. They also suppressed the transcription activity of survivin, a representative anti-apoptotic factor, and induced apoptosis in this cell line. Furthermore, using BALB/C nude mice with xenografts of AtT20 cells in vivo, we found that the combined administration of DHEA and PRT significantly attenuated tumor growth and survivin expression. The treatment also decreased the elevated plasma corticosterone levels and ameliorated the malnutrition induced by tumor growth. Altogether, these results suggested that combined treatments of DHEA and PRT potently inhibit the growth and function of corticotroph tumor cells both in vitro and in vivo. This effect may, at least partly, be caused by the suppressive effects of these compounds, such as survivin and other inhibitor of apoptosis proteins, on NF-κB-mediated gene transcription.

p125 focal adhesion kinase promotes malignant astrocytoma cell proliferation in vivo

2000 ◽  
Vol 113 (23) ◽  
pp. 4221-4230 ◽  
Author(s):  
D. Wang ◽  
J.R. Grammer ◽  
C.S. Cobbs ◽  
J.E. Stewart ◽  
Z. Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Focal Adhesion ◽  
Fold Increase ◽  
Astrocytic Tumor ◽  
Malignant Astrocytoma

p125 focal adhesion kinase (p125FAK) is a cytoplasmic tyrosine kinase that is activated upon engagement of integrin cell adhesion receptors, and initiates several signaling events that modulate cell function in vitro. To determine the biologic role of p125FAK in malignant astrocytic tumor cells, U-251MG human malignant astrocytoma cells were stably transfected with p125FAK cDNA using the TET-ON system, and stable clones isolated that exhibited an estimated 5- or 20-fold increase in p125FAK expression on administration of 0.1 or 2.0 microg/ml doxycycline, respectively. In vitro studies demonstrated that induction of p125FAK resulted in a 2- to 3-fold increase in cell migration, increased p130CAS phosphorylation, localization of exogenous p125FAK to focal adhesions, and a 2-fold increase in soft agar growth. To determine the role of p125FAK in vivo, clones were injected stereotactically into the brains of scid mice. A 4.5-fold estimated increase in p125FAK expression was induced by administration of doxycycline in the drinking water. Analysis of xenograft brains demonstrated that, upon induction of p125FAK, there was a 1.6- to 2.8-fold increase in tumor cell number, and an increase in mAb PCNA-labeling of tumor cells in the absence of a change in the apoptotic index. Compared to normal brain, the expression of p125FAK was elevated in malignant astrocytic tumor biopsies from patient samples. These data demonstrate for the first time that p125FAK promotes tumor cell proliferation in vivo, and that the underlying mechanism is not associated with a reduction in apoptosis.

scholarly journals Clusterin and FOXL2 Act Concordantly to Regulate Pituitary Gonadotroph Adenoma Growth

2012 ◽  
Vol 26 (12) ◽  
pp. 2092-2103 ◽  
Author(s):  
Vera Chesnokova ◽  
Svetlana Zonis ◽  
Kolja Wawrowsky ◽  
Yuji Tani ◽  
Anat Ben-Shlomo ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Cell ◽  
Pituitary Tumor ◽  
Kinase Inhibitors ◽  
Tumor Development ◽  
Gene Promoter ◽  
Pituitary Tumors ◽  
Pituitary Cell ◽  
Forkhead Transcription Factor

Abstract Pituitary tumors grow slowly and despite their high prevalence are invariably benign. We therefore studied mechanisms underlying pituitary tumor growth restraint. Pituitary tumor transforming gene (PTTG), the index human securin, a hallmark of pituitary tumors, triggers pituitary cell proliferation and murine pituitary tumor development. We show that human gonadotroph cell pituitary tumors, unlike other secreting tumor types, express high levels of gonadotroph-specific forkhead transcription factor FOXL2, and both PTTG and Forkhead box protein L2 (FOXL2) stimulate gonadotroph clusterin (Clu) expression. Both Clu RNA isoforms are abundantly expressed in these nonhormone-secreting human tumors, and, when cultured, these tumor cells release highly abundant levels of secreted Clu. FOXL2 directly stimulates the Clu gene promoter, and we show that PTTG triggers ataxia telangiectasia mutated kinase/IGF-I/p38MAPK DNA damage/chromosomal instability signaling, which in turn also induces Clu expression. Consequently, Clu restrains pituitary cell proliferation by inducing cyclin dependent kinase inhibitors p16 and p27, whereas Clu deletion down-regulates p16 and p27 in the Clu−/− mouse pituitary. FOXL2 binds and suppresses the PTTG promoter, and Clu also suppresses PTTG expression, thus neutralizing protumorigenic PTTG gonadotroph tumor cell properties. In vivo, murine gonadotroph LβT2 tumor cell xenografts overexpressing Clu and FOXL2 both grow slower and elicit smaller tumors. Thus, gonadotroph tumor cell proliferation is determined by the interplay between cell-specific FOXL2 with PTTG and Clu.

scholarly journals Tumor cell-intrinsic PD-1 receptor is a tumor suppressor and mediates resistance to PD-1 blockade therapy

2020 ◽  
Vol 117 (12) ◽  
pp. 6640-6650 ◽  
Author(s):  
Xiaodong Wang ◽  
Xiaohui Yang ◽  
Chang Zhang ◽  
Yang Wang ◽  
Tianyou Cheng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Tumor Growth ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Colony Formation ◽  
Immune Escape ◽  
Potential Biomarker

The programmed cell death 1 (PD-1) receptor on the surface of immune cells is an immune checkpoint molecule that mediates the immune escape of tumor cells. Consequently, antibodies targeting PD-1 have shown efficacy in enhancing the antitumor activity of T cells in some types of cancers. However, the potential effects of PD-1 on tumor cells remain largely unknown. Here, we show that PD-1 is expressed across a broad range of tumor cells. The silencing of PD-1 or its ligand, PD-1 ligand 1 (PD-L1), promotes cell proliferation and colony formation in vitro and tumor growth in vivo. Conversely, overexpression of PD-1 or PD-L1 inhibits tumor cell proliferation and colony formation. Moreover, blocking antibodies targeting PD-1 or PD-L1 promote tumor growth in cell cultures and xenografts. Mechanistically, the coordination of PD-1 and PD-L1 activates its major downstream signaling pathways including the AKT and ERK1/2 pathways, thus enhancing tumor cell growth. This study demonstrates that PD-1/PD-L1 is a potential tumor suppressor and potentially regulates the response to anti-PD-1/PD-L1 treatments, thus representing a potential biomarker for the optimal cancer immunotherapeutic treatment.

scholarly journals Periprosthetic Osteolysis: Mechanisms, Prevention and Treatment

2019 ◽  
Vol 8 (12) ◽  
pp. 2091 ◽  
Author(s):  
Stuart B. Goodman ◽  
Jiri Gallo
Keyword(s):  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Periprosthetic Osteolysis ◽  
Bone Implant ◽  
Joint Replacements ◽  
In Vivo Experiments ◽  
Mechanical Factors

Clinical studies, as well as in vitro and in vivo experiments have demonstrated that byproducts from joint replacements induce an inflammatory reaction that can result in periprosthetic osteolysis (PPOL) and aseptic loosening (AL). Particle-stimulated macrophages and other cells release cytokines, chemokines, and other pro-inflammatory substances that perpetuate chronic inflammation, induce osteoclastic bone resorption and suppress bone formation. Differentiation, maturation, activation, and survival of osteoclasts at the bone–implant interface are under the control of the receptor activator of nuclear factor kappa-Β ligand (RANKL)-dependent pathways, and the transcription factors like nuclear factor κB (NF-κB) and activator protein-1 (AP-1). Mechanical factors such as prosthetic micromotion and oscillations in fluid pressures also contribute to PPOL. The treatment for progressive PPOL is only surgical. In order to mitigate ongoing loss of host bone, a number of non-operative approaches have been proposed. However, except for the use of bisphosphonates in selected cases, none are evidence based. To date, the most successful and effective approach to preventing PPOL is usage of wear-resistant bearing couples in combination with advanced implant designs, reducing the load of metallic and polymer particles. These innovations have significantly decreased the revision rate due to AL and PPOL in the last decade.

In Vitro and in Vivo Nuclear Factor-κB Inhibitory Effects of the Cell-Penetrating Penetratin Peptide

2006 ◽  
Vol 69 (6) ◽  
pp. 2027-2036 ◽  
Author(s):  
Tamás Letoha ◽  
Erzsébet Kusz ◽  
Gábor Pápai ◽  
Annamária Szabolcs ◽  
József Kaszaki ◽  
...  
Keyword(s):  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Inhibitory Effects ◽  
Cell Penetrating

Fucoidans from Cucumaria frondosa ameliorates renal interstitial fibrosis via inhibition of PI3K/Akt/NF-κB signaling pathway

2022 ◽  
Author(s):  
Zhuo-yue Song ◽  
Mengru Zhu ◽  
Jun Wu ◽  
Tian Yu ◽  
Yao Chen ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Interstitial Fibrosis ◽  
Protein Kinase B ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Renal Interstitial Fibrosis ◽  
Cucumaria Frondosa

The effects of Cucumaria frondosa polysaccharides (CFP) on renal interstitial fibrosis via regulating phosphatidylinositol-3-hydroxykinase/protein kinase-B/Nuclear factor-κB (PI3K/AKT/NF-κB) signaling pathway were investigated in vivo and in vitro in this research. A...

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