scholarly journals Inhibition of the Heat Shock Protein A (HSPA) Family Potentiates the Anticancer Effects of Manumycin A

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1418
Author(s):  
Damian Robert Sojka ◽  
Sylwia Hasterok ◽  
Natalia Vydra ◽  
Agnieszka Toma-Jonik ◽  
Anna Wieczorek ◽  
...  
Keyword(s):  
Heat Shock ◽  
Cancer Cells ◽  
Protein A ◽  
Heat Shock Factor 1 ◽  
Mcf7 Cells ◽  
In Vivo Models ◽  
Genetic Ablation ◽  
Anticancer Effects

Manumycin A (MA) is a well-tolerated natural antibiotic showing pleiotropic anticancer effects in various preclinical in vitro and in vivo models. Anticancer drugs may themselves act as stressors to induce the cellular adaptive mechanism that can minimize their cytotoxicity. Heat shock proteins (HSPs) as cytoprotective factors can counteract the deleterious effects of various stressful stimuli. In this study, we examined whether the anticancer effects of MA can be counteracted by the mechanism related to HSPs belonging to the HSPA (HSP70) family. We found that MA caused cell type-specific alterations in the levels of HSPAs. These changes included concomitant upregulation of the stress-inducible (HSPA1 and HSPA6) and downregulation of the non-stress-inducible (HSPA2) paralogs. However, neither HSPA1 nor HSPA2 were necessary to provide protection against MA in lung cancer cells. Conversely, the simultaneous repression of several HSPA paralogs using pan-HSPA inhibitors (VER-155008 or JG-98) sensitized cancer cells to MA. We also observed that genetic ablation of the heat shock factor 1 (HSF1) transcription factor, a main transactivator of HSPAs expression, sensitized MCF7 cells to MA treatment. Our study reveals that inhibition of HSF1-mediated heat shock response (HSR) can improve the anticancer effect of MA. These observations suggest that targeting the HSR- or HSPA-mediated adaptive mechanisms may be a promising strategy for further preclinical developments.

scholarly journals Phosphorylation of Serine 303 Is a Prerequisite for the Stress-Inducible SUMO Modification of Heat Shock Factor 1

2003 ◽  
Vol 23 (8) ◽  
pp. 2953-2968 ◽  
Author(s):  
Ville Hietakangas ◽  
Johanna K. Ahlskog ◽  
Annika M. Jakobsson ◽  
Maria Hellesuo ◽  
Niko M. Sahlberg ◽  
...  
Keyword(s):  
Heat Shock ◽  
Phosphorylation Site ◽  
Stress Granules ◽  
Heat Shock Factor ◽  
Transcriptional Level ◽  
Heat Shock Factor 1 ◽  
Protection Mechanism ◽  
Sumo Modification

ABSTRACT The heat shock response, which is accompanied by a rapid and robust upregulation of heat shock proteins (Hsps), is a highly conserved protection mechanism against protein-damaging stress. Hsp induction is mainly regulated at transcriptional level by stress-inducible heat shock factor 1 (HSF1). Upon activation, HSF1 trimerizes, binds to DNA, concentrates in the nuclear stress granules, and undergoes a marked multisite phosphorylation, which correlates with its transcriptional activity. In this study, we show that HSF1 is modified by SUMO-1 and SUMO-2 in a stress-inducible manner. Sumoylation is rapidly and transiently enhanced on lysine 298, located in the regulatory domain of HSF1, adjacent to several critical phosphorylation sites. Sumoylation analyses of HSF1 phosphorylation site mutants reveal that specifically the phosphorylation-deficient S303 mutant remains devoid of SUMO modification in vivo and the mutant mimicking phosphorylation of S303 promotes HSF1 sumoylation in vitro, indicating that S303 phosphorylation is required for K298 sumoylation. This finding is further supported by phosphopeptide mapping and analysis with S303/7 phosphospecific antibodies, which demonstrate that serine 303 is a target for strong heat-inducible phosphorylation, corresponding to the inducible HSF1 sumoylation. A transient phosphorylation-dependent colocalization of HSF1 and SUMO-1 in nuclear stress granules provides evidence for a strictly regulated subnuclear interplay between HSF1 and SUMO.

Abstract 19363: Migration of MicroRNAs From Cardiomyocytes to Cancer Cells Interferes With Tumor Formation in the Adult Heart

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Laura Graciotti ◽  
Toru Hosoda ◽  
Fumihiro Sanada ◽  
Giulia Borghetti ◽  
Christian Arranto ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Critical Role ◽  
Tumor Formation ◽  
Molecular Characteristics ◽  
Cardiac Tumors ◽  
Mcf7 Cells ◽  
Tissue Pressure ◽  
Intramyocardial Injection

The low incidence of cardiac tumors has been attributed to tissue pressure dictated by myocardial mechanics and large coronary blood flow. These variables, however, have failed to consider the possibility that the rare occurrence of heart neoplasms may be dictated by the molecular characteristics of cardiomyocytes. We have shown that miR-1, miR-133a, and miR-499 translocate from myocytes to co-cultured MCF7 breast cancer cells, inhibiting their growth. The transfer of miRs is mediated by gap junction channels and is abolished by Cx43 and Cx45 silencing. Although these in vitro results provided important information on the inhibitory function of miRs in cell proliferation, co-culture of myocytes and cancer cells does not mimic the in vivo organization of the myocardium that allows the formation of multiple sites of coupling between myocytes and tumor cells. To reproduce, at least in part, the in vivo condition, we developed first a physiological model of organ culture. Thick vibratome-cut myocardial slices were placed on a multiwell plate containing an oxygen-saturated sponge. At 24-48 hours, the cultured tissue was viable and myocytes showed a well organized sarcomere structure. Two hours after plating of the organ slices, control MCF7 cells or MCF7 cells in which Cx43 and Cx45 were silenced (MCF7-shCx43-shCx45) were seeded on the myocardium. Control MCF7 cells showed a slower growth rate than MCF7-shCx43-shCx45 cells, a finding consistent with miR translocation and its blockade, respectively. Second, 1 x 106 MCF7 or MCF7 cells overexpressing miR-1, miR-133a, and miR-499 (MCF7-miRs) were injected subcutaneously in NOD-SCID mice; ~45 days later, the tumors developed from MCF7 cells were more than 10-fold larger and 3-fold heavier than those originated from MCF7-miRs cells. Third, these studies were complemented with the intramyocardial injection of 1 x 105 control MCF7 cells. Five weeks later, no neoplastic lesions were identified. However, when an excessive number of MCF7 cells were injected, 1 x 106, tumor formation was apparent. In conclusion, our results indicate that transfer of miR-1, miR-133a, and miR-499 from cardiomyocytes to cancer cells plays a critical role in preventing the generation of tumors in the myocardium.

MP73-10 RITONAVIR, A POTENT INHIBITOR OF CYP3A4, ENHANCES THE ANTICANCER EFFECTS OF ENTINOSTAT IN RENAL CANCER CELLS IN VITRO AND IN VIVO

2017 ◽  
Vol 197 (4S) ◽  
Author(s):  
Takako Asano ◽  
Akinori Sato ◽  
Kazuki Okubo ◽  
Makoto Isono ◽  
Tomohiko Asano
Keyword(s):  
Cancer Cells ◽  
Renal Cancer ◽  
Potent Inhibitor ◽  
Anticancer Effects

A new variant of the heat shock protein GRP78 as target for antibody- treatment of pancreatic cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21173-21173
Author(s):  
H. Vollmers ◽  
N. Rauschert ◽  
L. Rasche ◽  
F. Hensel ◽  
S. Brändlein
Keyword(s):  
Heat Shock ◽  
Cancer Cells ◽  
Oxidized Ldl ◽  
Human Monoclonal Antibody ◽  
Cell Cancer ◽  
Antibody Treatment ◽  
Surface Protection ◽  
New Variant

21173 Background: Pancreatic malignancies belong to the top-five killers among all cancers worldwide. The 5-year survival rate with conventional therapy is below 5%. This shows that there is a big need for new therapeutical approaches. The fully human monoclonal antibody SAM-6 is a germ-line coded IgM, isolated from a cancer patient by TRIOMA technology. SAM-6 antibody binds to a modified O-linked carbohydrate moiety expressed on a membrane-bound variant of GRP78, which is a member of the HSP70 family. Heat-shock proteins (HSPs) are critical components of a cell's defense mechanism against injury associated with adverse stresses. They can protect cells against subsequent, otherwise lethal, outcome. Although HSPs are very beneficial to the normal cell, cancer cells often over-express HSPs on the membrane. They use them in response to stresses associated with various therapies, diminishing the treatment effects. Methods: In vitro and in vivo assays were used to investigate the apoptotic effects of antibody SAM-6 on pancreas cancer cells. Results: Binding of SAM-6 antibody to GRP78 induces an overfeeding of malignant cells with oxidized LDL. The cancer cells over-accumulate depots of cholesterol and triglyceride esters and finally undergo apoptosis. The deadly effect of SAM-6 could be demonstrated in vitro and in vivo in experimental animal models. Conclusions: These data show that cancer-specific modifications of cell surface protection molecules are ideal targets for immuno-therapeutical approaches. No significant financial relationships to disclose.

Preclinical investigation of a small molecule inhibitor of p300/CBP reveals efficacy in patient-derived prostate tumor explants.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16534-e16534 ◽  
Author(s):  
Lisa Butler ◽  
Swati Irani ◽  
Margaret Centenera ◽  
Natalie Ryan ◽  
Neil Pegg ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Small Molecule ◽  
Single Agent ◽  
Specific Antigen ◽  
Resistance Mechanisms ◽  
Prostate Cancer Cells ◽  
In Vivo Models

e16534 Background: Growth and survival of prostate cancer cells are initially dependent upon androgens, and androgen deprivation therapy (ADT) is used to control tumor growth. Unfortunately, resistance to ADT inevitably occurs, and patients relapse with lethal castrate-resistant prostate cancer (CRPC). Increased expression of the androgen receptor (AR) and constitutively active AR variants are hallmarks of CRPC, and treatments targeting aberrant AR signaling are urgently required. CCS1477 is an inhibitor of p300/CBP currently in a Phase I/IIa study for CRPC. CCS1477 enhances degradation of numerous cellular proteins including the AR and AR variants in prostate cancer cells. Our preclinical studies with this compound demonstrated potent single-agent efficacy of CCS1477 using in vitro and in vivo models of prostate cancer and, when used in combination, CCS1477 enhances the efficacy of enzalutamide, a clinical AR antagonist. Understanding the response of clinical tumors to CCS1477, and their potential adaptive evolution, is essential to personalize treatment and predict potential resistance mechanisms. Methods: To assess CCS1477 in human disease, we used a unique model in which clinical prostate tumors from radical prostatectomy are cultured as explants with maintenance of tissue integrity, cell proliferation and androgen signaling. Tumors from 13 patients were cultured in the absence or presence of CCS1477 (10µM) or enzalutamide (10µM) for 48 or 72 hours; micromolar doses were selected to account for altered small molecule uptake and penetration into tissues compared to cell lines, as previously reported. Proliferation, apoptosis and androgen signaling were all analyzed post-culture. Results: Whereas the tumor explants exhibited highly heterogenous proliferative responses to enzalutamide, tumors from all patients exhibited a marked antiproliferative response to CCS1477 (mean reduction in Ki67 immunoreactivity of > 90% compared to vehicle control; p < 0.0005). Culture with CCS1477 was associated with repression of androgen signaling in the prostate tissues, measured by expression and secretion of the clinical biomarker prostate specific antigen (PSA). Conclusions: The consistent and pronounced efficacy of CCS1477 in this patient-derived model would support further investigation of this class of epigenetic agents in the castrate-sensitive prostate cancer setting.

Differential Neuroprotection from Human Heat Shock Protein 70 Overexpression in in Vitro and in Vivo Models of Ischemia and Ischemia-like Conditions

2001 ◽  
Vol 170 (1) ◽  
pp. 129-139 ◽  
Author(s):  
Jong Eun Lee ◽  
Midori A. Yenari ◽  
Guo Hua Sun ◽  
Lijun Xu ◽  
Michelle R. Emond ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Heat Shock Protein 70 ◽  
In Vivo Models ◽  
Human Heat Shock Protein

Resveratrol improves the anticancer effects of doxorubicin in vitro and in vivo models: A mechanistic insight

Phytomedicine ◽  
2016 ◽  
Vol 23 (3) ◽  
pp. 233-242 ◽  
Author(s):  
Girish Rai ◽  
Sanjay Mishra ◽  
Shankar Suman ◽  
Yogeshwer Shukla
Keyword(s):  
In Vivo Models ◽  
Anticancer Effects ◽  
Mechanistic Insight

scholarly journals Estrogen deprivation triggers an immunosuppressive phenotype in breast cancer cells

2019 ◽  
Author(s):  
Daniela Hühn ◽  
Pablo Martí-Rodrigo ◽  
Silvana Mouron ◽  
Catherine S. Hansel ◽  
Kirsten Tschapalda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Mcf7 Cells ◽  
Estrogen Deprivation ◽  
Er Positive

ABSTRACTEstrogen receptor (ER)-positive breast tumors are routinely treated with estrogen-depriving therapies. Despite their effectiveness, patients often progress into a more aggressive form of the disease. Through a chemical screen oriented to identify chemicals capable of inducing the expression of the immune-checkpoint ligand PD-L1, we found antiestrogens as hits. Subsequent validations confirmed that estrogen deprivation or ERα depletion induces PD-L1 expression in ER-positive breast cancer cells, both in vitro and in vivo. Likewise, PD-L1 expression is increased in metastasis arising from breast cancer patients receiving adjuvant hormonal therapy for their local disease. Transcriptome analyses indicate that estrogen deprivation triggers a broad immunosuppressive program, not restricted to PD-L1. Accordingly, estrogen deprived MCF7 cells are resistant to T-cell mediated cell killing, in a manner that can be reverted by estradiol. Our study reveals that while antiestrogen therapies effectively limit tumor growth in ER-positive breast cancers, they also trigger a transcriptional program that favors immune evasion.

scholarly journals A Mesenchymal-like Program of Dormancy controlled by ZFP281 Serves as a Barrier To Metastatic Progression of Early Disseminated Cancer Cells

2021 ◽  
Author(s):  
Julio Aguirre-Ghiso ◽  
Ana Rita Nobre ◽  
Erica Dalla ◽  
Jihong Yang ◽  
Xin Huang ◽  
...  
Keyword(s):  
Single Cell ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Metastatic Progression ◽  
In Vivo Models ◽  
Primary Tumors ◽  
Rate Limiting Step ◽  
Metastasis Models

Abstract Increasing evidence shows that cancer cells can disseminate from early-evolved primary lesions much earlier than the classical metastasis models predicted. It is thought that a state of early disseminated cancer cell (early DCC) dormancy can precede genetic maturation of DCCs and metastasis initiation. Here we reveal at single cell resolution a previously unrecognized role of mesenchymal- and pluripotency-like programs in coordinating early cancer cell spread and a long-lived dormancy program in early DCCs. Using in vitro and in vivo models of invasion and metastasis, single cell RNA sequencing and human sample analysis, we provide unprecedented insight into how early DCC heterogeneity and plasticity control the timing of reactivation. We identify in early lesions and early DCCs the transcription factor ZFP281 as an inducer of mesenchymal- and primed pluripotency-like programs, which is absent in advanced primary tumors and overt metastasis. ZFP281 not only controls the early spread of cancer cells but also locks early DCCs in a prolonged dormancy state by preventing the acquisition of an epithelial-like proliferative program and consequent metastasis outgrowth. Thus, ZFP281-driven dormancy of early DCCs may be a rate-limiting step in metastatic progression functioning as a first barrier that DCCs must overcome to then undergo genetic maturation.

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