scholarly journals Siah2 control of T-regulatory cells limits anti-tumor immunity

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Marzia Scortegagna ◽  
Kathryn Hockemeyer ◽  
Igor Dolgalev ◽  
Joanna Poźniak ◽  
Florian Rambow ◽  
...  
Keyword(s):  
Tumor Immunity ◽  
Cell Cycle Progression ◽  
T Regulatory Cells ◽  
Kinase Inhibitor ◽  
G1 Arrest ◽  
Cancer Therapies ◽  
Activated T Cells ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Elevated Expression

AbstractUnderstanding the mechanisms underlying anti-tumor immunity is pivotal for improving immune-based cancer therapies. Here, we report that growth of BRAF-mutant melanoma cells is inhibited, up to complete rejection, in Siah2−/− mice. Growth-inhibited tumors exhibit increased numbers of intra-tumoral activated T cells and decreased expression of Ccl17,Ccl22, and Foxp3. Marked reduction in Treg proliferation and tumor infiltration coincide with G1 arrest in tumor infiltrated Siah2−/− Tregs in vivo or following T cell stimulation in culture, attributed to elevated expression of the cyclin-dependent kinase inhibitor p27, a Siah2 substrate. Growth of anti-PD-1 therapy resistant melanoma is effectively inhibited in Siah2−/− mice subjected to PD-1 blockade, indicating synergy between PD-1 blockade and Siah2 loss. Low SIAH2 and FOXP3 expression is identified in immune responsive human melanoma tumors. Overall, Siah2 regulation of Treg recruitment and cell cycle progression effectively controls melanoma development and Siah2 loss in the host sensitizes melanoma to anti-PD-1 therapy.

Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 3138-3147 ◽  
Author(s):  
Thomas Strömberg ◽  
Anna Dimberg ◽  
Anna Hammarberg ◽  
Kristina Carlson ◽  
Anders Österborg ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Intracellular Signaling ◽  
Kinase Inhibitor ◽  
Mammalian Target Of Rapamycin ◽  
G1 Arrest ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Induced Apoptosis ◽  
Molecular Mode

Abstract Circumvention of chemoresistance in the B-cell neoplasm multiple myeloma (MM) might be achieved by targeting certain intracellular signaling pathways crucial for survival of the malignant clone. The use of the macrolide rapamycin, selectively inhibiting the phosphoprotein mammalian target of rapamycin (mTOR) downstream of, for example, insulin-like growth factor-I receptor (IGF-IR), possibly represents such a molecular mode of therapy. By using a panel of MM cell lines we showed that rapamycin induced G0/G1 arrest, an effect being associated with an increase of the cyclin-dependent kinase inhibitor p27 and a decrease of cyclins D2 and D3. Interestingly, in primary, mainly noncycling MM cells, rapamycin, at clinically achievable concentrations, induced apoptosis. More important, rapamycin sensitized both MM cell lines and primary MM cells to dexamethasone-induced apoptosis. This effect was associated with a decreased expression of cyclin D2 and survivin. The phosphorylation of the serine/threonine kinase p70S6K at Thr389 and Thr421/Ser424 was down-regulated by rapamycin and/or dexamethasone. Strikingly, the combinatorial treatment with rapamycin and dexamethasone suppressed the antiapoptotic effects of exogenously added IGF-I and interleukin 6 (IL-6) as well as their stimulation of p70S6K phosphorylation. The induction of apoptosis by rapamycin and dexamethasone despite the presence of survival factors was also demonstrated in primary MM cells, thus suggesting this drug combination to be active also in vivo. (Blood. 2004;103:3138-3147)

scholarly journals Combination Gene Delivery of the Cell Cycle Inhibitor p27 with Thymidine Kinase Enhances Prodrug Cytotoxicity

1998 ◽  
Vol 72 (11) ◽  
pp. 9201-9207 ◽  
Author(s):  
Xavier Danthinne ◽  
Kazunori Aoki ◽  
Akiko L. Kurachi ◽  
Gary J. Nabel ◽  
Elizabeth G. Nabel
Keyword(s):  
Cell Cycle ◽  
Gene Transfer ◽  
Thymidine Kinase ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Genetically Modified ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Cyclin Dependent Kinase Inhibitor

ABSTRACT Cytoxicity induced by the herpesvirus thymidine kinase (TK) gene in combination with prodrugs is dependent on cell growth and leads to the elimination of genetically modified cells, thus limiting the duration of expression and efficacy of this treatment in vivo. Here, an effort was made to enhance TK/prodrug efficacy by coexpression of a cyclin-dependent kinase inhibitor (CKI), p27, to render cells resistant to TK/prodrug by inhibiting DNA synthesis. Expression of p27 by transfection substantially reduced cell cycle progression, and its activity was enhanced by mutations designed to stabilize the protein. Coexpression of p27 and TK or a p27/TK fusion protein led to greater prodrug cytotoxicity than that produced by TK alone in the Renca cell line, which is sensitive to bystander killing. Combination gene transfer of this CKI with TK therefore sustained the synthesis of TK by genetically modified cells to enhance the susceptibility of bystander cells to prodrug cytotoxicity and increased the efficacy of this gene transfer approach.

Role of p21Cip1/Waf1 in cell-cycle exit of endomitotic megakaryocytes

Blood ◽  
2001 ◽  
Vol 98 (12) ◽  
pp. 3274-3282 ◽  
Author(s):  
Véronique Baccini ◽  
Lydia Roy ◽  
Natacha Vitrat ◽  
Hédia Chagraoui ◽  
Siham Sabri ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Kinase Inhibitor ◽  
Cyclin D3 ◽  
Reciprocal Relation ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Elevated Expression ◽  
High Level ◽  
Megakaryocyte Differentiation

Abstract The cyclin-dependent kinase inhibitor p21Waf-1/Cip-1 is expressed at high level during megakaryocyte differentiation, but its precise function remains unknown. In this study, it is confirmed that p21 was expressed at a high level in hypoploid (2N and 4N) and polyploid (at least 8N) human megakaryocytes derived from CD34+ cells. A high expression of p27Kip1, p16, cyclin E, and cyclin D3 was also found in both populations associated with a hypophosphorylated form of retinoblastoma protein, suggesting that the majority of hypoploid and polyploid megakaryocytes are G1-arrested cells. As human megakaryocytes grown in vitro present a defect in their polyploidization, the study switched to the murine model. The modal ploidy of megakaryocytes derived from lineage-negative cells was 32N, and an elevated expression of p21 was found in high-ploidy megakaryocytes. In addition, p21 and p27 were coexpressed in the majority of mature polyploid megakaryocytes. The p21 was detected by immunofluorescence in megakaryocytes derived from p53−/− mice, demonstrating a p53-independent regulation during megakaryocyte differentiation. Megakaryocytopoiesis of p21−/− mice was subsequently studied. No marked abnormality in the ploidy of primary or cultured megakaryocytes was detected. Overexpression of p21 in p21−/− or normal murine megakaryocytes and in human megakaryocytes showed in all these cases a marked inhibition in megakaryocyte polyploidization. In conclusion, while a reciprocal relation is observed between p21 levels in megakaryocytes and the cycling state of the cells, p21 is not essential for the determination of the ploidy profile in normal megakaryocytes in vivo. However, high levels of its expression in cultured megakaryocytes arrest the endomitotic cell cycle.

scholarly journals Discovery of vanoxerine dihydrochloride as a CDK2/4/6 triple-inhibitor for the treatment of human hepatocellular carcinoma

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Ying Zhu ◽  
Kun-Bin Ke ◽  
Zhong-Kun Xia ◽  
Hong-Jian Li ◽  
Rong Su ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle Progression ◽  
G1 Arrest ◽  
Huh7 Cells ◽  
Synergistic Cytotoxicity ◽  
Combination Study ◽  
Experimental Approaches ◽  
Induced Apoptosis

Abstract Background Cyclin-dependent kinases 2/4/6 (CDK2/4/6) play critical roles in cell cycle progression, and their deregulations are hallmarks of hepatocellular carcinoma (HCC). Methods We used the combination of computational and experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for the treatment of HCC. Results We identified vanoxerine dihydrochloride as a new CDK2/4/6 inhibitor, and a strong cytotoxicdrugin human HCC QGY7703 and Huh7 cells (IC50: 3.79 μM for QGY7703and 4.04 μM for Huh7 cells). In QGY7703 and Huh7 cells, vanoxerine dihydrochloride treatment caused G1-arrest, induced apoptosis, and reduced the expressions of CDK2/4/6, cyclin D/E, retinoblastoma protein (Rb), as well as the phosphorylation of CDK2/4/6 and Rb. Drug combination study indicated that vanoxerine dihydrochloride and 5-Fu produced synergistic cytotoxicity in vitro in Huh7 cells. Finally, in vivo study in BALB/C nude mice subcutaneously xenografted with Huh7 cells, vanoxerine dihydrochloride (40 mg/kg, i.p.) injection for 21 days produced significant anti-tumor activity (p < 0.05), which was comparable to that achieved by 5-Fu (10 mg/kg, i.p.), with the combination treatment resulted in synergistic effect. Immunohistochemistry staining of the tumor tissues also revealed significantly reduced expressions of Rb and CDK2/4/6in vanoxerinedihydrochloride treatment group. Conclusions The present study isthe first report identifying a new CDK2/4/6 triple inhibitor vanoxerine dihydrochloride, and demonstrated that this drug represents a novel therapeutic strategy for HCC treatment.

scholarly journals Asciminib Mitigates DNA Damage Stress Signaling Induced by Cyclophosphamide in the Ovary

2021 ◽  
Vol 22 (3) ◽  
pp. 1395
Author(s):  
Luca Mattiello ◽  
Giulia Pucci ◽  
Francesco Marchetti ◽  
Marc Diederich ◽  
Stefania Gonfloni
Keyword(s):  
Ovarian Reserve ◽  
Kinase Inhibitor ◽  
Concomitant Administration ◽  
Cancer Therapies ◽  
Cancer Treatments ◽  
Abl Tyrosine Kinase ◽  
Negative Impacts ◽  
Abl Tyrosine Kinase Inhibitor

Cancer treatments can often adversely affect the quality of life of young women. One of the most relevant negative impacts is the loss of fertility. Cyclophosphamide is one of the most detrimental chemotherapeutic drugs for the ovary. Cyclophosphamide may induce the destruction of dormant follicles while promoting follicle activation and growth. Herein, we demonstrate the in vivo protective effect of the allosteric Bcr-Abl tyrosine kinase inhibitor Asciminib on signaling pathways activated by cyclophosphamide in mouse ovaries. We also provide evidence that Asciminib does not interfere with the cytotoxic effect of cyclophosphamide in Michigan Cancer Foundation (MCF)7 breast cancer cells. Our data indicate that concomitant administration of Asciminib mitigates the cyclophosphamide-induced ovarian reserve loss without affecting the anticancer potential of cyclophosphamide. Taken together, these observations are relevant for the development of effective ferto-protective adjuvants to preserve the ovarian reserve from the damaging effects of cancer therapies.

Functional Loss of p21/Waf-1 in a Case of Benign Canine Multicentric Melanoma

1998 ◽  
Vol 35 (2) ◽  
pp. 94-101 ◽  
Author(s):  
M. G. Ritt ◽  
J. Wojcieszyn ◽  
J. F. Modiano
Keyword(s):  
Tumor Suppressor ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
P53 Gene ◽  
Tumor Formation ◽  
Cyclin Dependent Kinase ◽  
P53 Expression ◽  
Functional Loss ◽  
Normal Tissues ◽  
Cyclin Dependent Kinase Inhibitor

Mutations of tumor suppressor genes remove mechanisms that normally arrest proliferation of transformed cells, resulting in tumor formation. The p53 gene product functions as a tumor suppressor that induces p21/Waf-1, the 21-kDa product of the waf-1/cip-1/mda-6 gene. p21/Waf-1 is a pan-cyclin-dependent kinase inhibitor that arrests cell cycle progression under a variety of circumstances. We examined tissues from a dog with multiple primary pigmented proliferative lesions (benign, multicentric melanoma consisting of three distinct dermal lesions and a matrical cyst) for p21/Waf-1 and p53 expression by immunohistochemistry and immunoblotting. p21/Waf-1 and p-53 proteins were undetectable in the tumor cells and in the cyst but were present in adjacent normal tissues. Abundant cyclin-dependent kinase 4 (Cdk4), a protein related functionally to p21/Waf-1, also was present in the cyst. A somatic mutation of the waf-1 gene or of the p53 gene may have resulted in the loss of p21/Waf-1 expression in a common precursor of pigment-producing cells from the affected dog. Furthermore, this functional loss of p21/Waf-1 may play an important role in the genesis of canine benign melanoma.

Paradoxical accumulation of the cyclin-dependent kinase inhibitor p27kip1 during the cAMP-dependent mitogenic stimulation of thyroid epithelial cells

1996 ◽  
Vol 109 (7) ◽  
pp. 1759-1764
Author(s):  
F. Depoortere ◽  
J.E. Dumont ◽  
P.P. Roger
Keyword(s):  
Cell Cycle ◽  
Epithelial Cells ◽  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Concomitant Administration ◽  
Growth Stimulation ◽  
Positive Control ◽  
Cycle Progression ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Enhanced Expression

In different systems, cAMP either blocks or promotes cell cycle progression in mid to late G1 phase. Dog thyroid epithelial cells in primary culture constitute a model of positive control of DNA synthesis initiation and G0-S pre-replicative phase progression by cyclic AMP (cAMP) as a second messenger for thyrotropin (TSH). We report here that TSH markedly increases the expression of p27kip1, the inhibitor of the cell cycle and cyclin-dependent kinases. This effect was prevented by the concomitant administration of the cAMP-independent mitogens, epidermal growth factor (EGF)+serum. EGF+serum also slightly inhibited the weak basal accumulation of p27kip1. Nevertheless, in the case of stimulation by TSH alone, the cAMP-dependent cell cycle progression was fully compatible with the enhanced expression of p27kip1. This observation is paradoxical since a decrease of p27kip1 is generally associated with growth stimulation in other systems, and since a similar cAMP-dependent increase of p27kip1 in macrophages has been found responsible for mid-G1 cell cycle arrest. The opposite regulation of p27kip1 in response to TSH or EGF+serum in dog thyroid epithelial cells suggests a major difference at mid to late G1 stages between cAMP-dependent and cAMP-independent mitogenic pathways.

scholarly journals Negative Regulation of ASK1 by p21Cip1 Involves a Small Domain That Includes Serine 98 That Is Phosphorylated by ASK1 In Vivo

2007 ◽  
Vol 27 (9) ◽  
pp. 3530-3541 ◽  
Author(s):  
Jun Zhan ◽  
John B. Easton ◽  
Shile Huang ◽  
Ashutosh Mishra ◽  
Limin Xiao ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Cellular Functions ◽  
Terminal Protein ◽  
Jnk Pathway ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Small Domain ◽  
Cellular Stresses

ABSTRACT The cyclin-dependent kinase inhibitor p21Cip1 regulates multiple cellular functions and protects cells from genotoxic and other cellular stresses. Activation of apoptosis signal-regulating kinase 1 (ASK1) induced by inhibition of mTOR signaling leads to sustained phospho-c-Jun that is suppressed in cells with functional p53 or by forced expression of p21Cip1. Here we show that small deletions of p21Cip1 around S98 abrogate its association with ASK1 but do not affect binding to Cdk1, hence distinguishing between the cell cycle-regulating functions of p21Cip1 and its ability to suppress activation of the ASK1/Jun N-terminal protein kinase (JNK) pathway. p21Cip1 is phosphorylated in vitro by both ASK1 and JNK1 at S98. In vivo phosphorylation of p21Cip1, predominantly carried out by ASK1, is associated with binding to ASK1 and inactivation of ASK1 kinase function. Binding of p21Cip1 to ASK1 requires ASK1 kinase function and may involve phosphorylation of S98.

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