Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Procaspase-3 Overexpression in Cancer: A Paradoxical Observation with Therapeutic Potential.

ABSTRACT: Many anticancer strategies rely on the promotion of apoptosis in cancer cells as a means to shrink tumors. Crucial for apoptotic function are executioner caspases, most notably caspase-3, that proteolyze a variety of proteins, inducing cell death. Paradoxically, overexpression of procaspase-3 (PC-3), the low-activity zymogen precursor to caspase-3, has been reported in a variety of cancer types. Until recently, this counterintuitive overexpression of a pro-apoptotic protein in cancer has been puzzling. Recent studies suggest subapoptotic caspase-3 activity may promote oncogenic transformation, a possible explanation for the enigmatic overexpression of PC-3. Herein, the overexpression of PC-3 in cancer and its mechanistic basis is reviewed; collectively, the data suggest the potential for exploitation of PC-3 overexpression with PC-3 activators as a targeted anticancer strategy.

SUBMITTER: Boudreau MW

PROVIDER: S-EPMC6858495 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Procaspase-3 Overexpression in Cancer: A Paradoxical Observation with Therapeutic Potential.

Boudreau Matthew W MW Peh Jessie J Hergenrother Paul J PJ

ACS chemical biology 20190716 11

Many anticancer strategies rely on the promotion of apoptosis in cancer cells as a means to shrink tumors. Crucial for apoptotic function are executioner caspases, most notably caspase-3, that proteolyze a variety of proteins, inducing cell death. Paradoxically, overexpression of procaspase-3 (PC-3), the low-activity zymogen precursor to caspase-3, has been reported in a variety of cancer types. Until recently, this counterintuitive overexpression of a pro-apoptotic protein in cancer has been pu ...[more]

PMID: 31260254

Similar Datasets

Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer.

Project description:Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression of FLIP, which blocks the extrinsic apoptotic pathway by inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression in NSCLC and the effect of HDAC inhibitors on FLIP expression, activation of caspase-8 and drug resistance in NSCLC and normal lung cell line models. Immunohistochemical analysis of cytoplasmic and nuclear FLIP and procaspase-8 protein expression was carried out using a novel digital pathology approach. Both FLIP and procaspase-8 were found to be significantly overexpressed in tumours, and importantly, high cytoplasmic expression of FLIP significantly correlated with shorter overall survival. Treatment with HDAC inhibitors targeting HDAC1-3 downregulated FLIP expression predominantly via post-transcriptional mechanisms, and this resulted in death receptor- and caspase-8-dependent apoptosis in NSCLC cells, but not normal lung cells. In addition, HDAC inhibitors synergized with TRAIL and cisplatin in NSCLC cells in a FLIP- and caspase-8-dependent manner. Thus, FLIP and procaspase-8 are overexpressed in NSCLC, and high cytoplasmic FLIP expression is indicative of poor prognosis. Targeting high FLIP expression using HDAC1-3 selective inhibitors such as entinostat to exploit high procaspase-8 expression in NSCLC has promising therapeutic potential, particularly when used in combination with TRAIL receptor-targeted agents.

| S-EPMC3877552 | biostudies-literature

HER2 Overexpression in Retinoblastoma: A Potential Therapeutic Target?

Project description:Background:Retinoblastoma (RB) is the most common primary intraocular malignancy. Current therapies are associated with high morbidity in the short- and long-term. Human epidermal growth factor receptor 2 (HER2) is a transmembrane protein detected in 15-30% of breast cancers, but it has also been described in other malignancies. Recently, it has been claimed that a truncated version of this protein is expressed in RB, responsive to directed therapies in vitro. We scored HER2 overexpression in RB tissue samples and discussed its potential clinical utility. Methods:HER2 overexpression was investigated using immunohistochemistry; the overexpression was evaluated with a score ranging from 0 to 3+ according to the membranous staining pattern in archival formalin-fixed, paraffin-embedded RBs. Results:A total of 60 RB cases and a RB cell line (Y79) were considered. The mean age at enucleation was 31.6 ± 31.5 months. The mean time from diagnosis to enucleation was 11.8 ± 11.2 months (range 1-44). Five (8%) cases were multifocal. HER2 overexpression was negative in all RB cases (49 cases scored 0 and 11 scored 1+) and in the Y79 cell line. Conclusions:Overall, we were not able to demonstrate the overexpression of HER2. Further studies should clarify and better elucidate the potential role of HER2-targeted therapies in RB.

| S-EPMC5649335 | biostudies-literature

The therapeutic potential of bedside art observation in hematologic cancer inpatients: a randomized controlled pilot study.

Project description:PurposePrior research has suggested that art-based interventions may reduce anxiety in cancer patients and enhance dialogue in the healthcare setting. Through implementing Art at the Bedside, an art-based hospital visitation program, we sought to examine whether dedicated art observation sessions, and varying formats (with and without guided discussion), could have therapeutic effects on cancer patients' mental wellbeing.MethodsThis randomized controlled pilot study evaluated the effects of bedside art observation on anxiety in a sample of 73 hematologic cancer inpatients. We compared state anxiety, as measured by an abbreviated form of the Spielberger State-Trait Anxiety Inventory (STAI Y-6), across three groups (participants who observed an electronic selection of artwork with and without guided discussion, and a control group that did not engage in either dedicated art observation activity).ResultsWe found that mean anxiety scores were significantly lower among those who participated in guided art observation, compared to those who did not (8.92 versus 12.1, scored on a scale of 6 to 24, p = 0.009, with a medium effect size (η2 = 12.7)). The majority of participants who engaged in art observation felt that the activity provided positive distraction (85.7%) and decreased boredom (79.6%), and many noted that it reduced feelings of anxiety (46.9%) and depression (24.5%).ConclusionThese findings suggest that bedside art observation, particularly with guided discussion, may be a promising complementary therapy for reducing cancer-related anxiety and improving the patient experience in the inpatient hematology/oncology setting, and would benefit from further inquiry.

| S-EPMC8754522 | biostudies-literature

Overexpression of IRS-4 Correlates with Procaspase 3 Levels in Tumoural Tissue of Patients with Colorectal Cancer.

Project description:We reported that insulin receptor substrate 4 (IRS-4) levels increased in tissue from colorectal cancer (CRC) patients and promoted retinoblastoma-cyclin-dependent kinase activation. The aim of the present study was to evaluate the effect of IRS-4 on IGF-1 receptor pathway and its impact on procaspase 3 and PARP expression in RKO and HepG2 cancer cell lines. The results obtained in vitro were compared with those obtained from biopsies of patients with CRC (n = 18), tubulovillous adenomas (TA) (n = 2) and in matched adjacent normal colorectal (MANC) tissue (n = 20). IRS-4 overexpression in cultured cells induced the overactivation of IGF-1/BRK/AKT/GSK-3/?-catenin/cyclin D1 pathways, which led to increased expression of procaspase 3 and PARP protein levels. Studies carried out on CRC and TA tissues revealed the overactivation of the IGF-1 receptor signalling pathway, as well as the overexpression of procaspase 3 and PARP in tumoural tissue with respect to MANC tissue. The upregulation of IRS-4 in tumoural samples correlated significantly with the increase in pIGF-1 receptor (Tyr 1165/1166) (r = 0.84; p < 0.0001), procaspase 3 (r = 0. 77; p < 0. 0005) and PARP (r = 0. 89; p < 0. 0005). Similarly, we observed an increase in the proteolysis of procaspase 3 in tumoural tissue with respect to MANC tissue, which correlated significantly with the degradation of PARP (r = 0.86; p < 0.0001), p53 (r = 0.84; p < 0.0001), and GSK-3 (r = 0.78; p < 0.0001). The stratification of patient samples using the TNM system revealed that procaspase 3 and caspase 3 increased gradually with T values, which suggests their involvement in the size and local invasion of primary tumours. Taken together, our findings suggest that IRS-4 overexpression promotes the activation of the IGF-1 receptor pathway, which leads to the increase in procaspase 3 levels in CRC.

| S-EPMC6206579 | biostudies-literature

PTTG1 overexpression in adrenocortical cancer is associated with poor survival and represents a potential therapeutic target.

Project description:BackgroundAdrenocortical carcinoma (ACC) is associated with poor survival rates. The objective of the study was to analyze ACC gene expression profiling data for prognostic biomarkers and therapeutic targets.MethodsWe profiled 44 ACC and 4 normal adrenals on Affymetrix U133 Plus 2 expression microarrays. Pathway and transcriptional enrichment analysis was performed. Protein levels were determined by Western blot. Drug efficacy was assessed against ACC cell lines. Previously published expression datasets were analyzed for validation.ResultsPathway enrichment analysis identified marked dysregulation of cyclin-dependent kinases and mitosis. Overexpression of PTTG1, which encodes securin, a negative regulator of p53, was identified as a marker of poor survival. Median survival for patients with tumors expressing high PTTG1 levels (log2 ratio of PTTG1 to average β-actin <-3.04) was 1.8 years compared with 9.0 years if tumors expressed lower levels of PTTG1 (P < .0001). Analysis of a previously published dataset confirmed the association of high PTTG1 expression with a poor prognosis. Treatment of 2 ACC cell lines with vorinostat decreased securin levels and inhibited cell growth (median inhibition concentrations of 1.69 μmol/L and 0.891 μmol/L, for SW-13 and H295R, respectively).ConclusionOverexpression of PTTG1 is correlated with poor survival in ACC. PTTG1/securin is a prognostic biomarker and warrants investigation as a therapeutic target.

| S-EPMC4054940 | biostudies-literature

Paradoxical role of interleukin-33/suppressor of tumorigenicity 2 in colorectal carcinogenesis: Progress and therapeutic potential.

Project description:Colorectal cancer (CRC) is presently the second most prevalent global mortality-inducing cancer. CRC carcinogenesis is a multifactorial process involving internal genetic mutations and the external environment. In addition, non-neoplastic cell activities within tumor microenvironments for CRC development have been established. However, interleukin (IL)-33, secreted by such cell types, plays a pivotal role in cancer progression due to interaction with cellular constituents within the tumor-inflammation microenvironment. IL-33 belongs to the IL-1 cytokine family and acts as binding attachments for the suppressor of tumorigenicity (ST)2 receptor. Therefore, how to coordinate tumor microenvironment, design and optimize treatment strategies suitable for CRC, based on IL-33/ST2 signal is a challenge. Even though it has established influences upon immunity-linked conditions, IL-33 effects on CRC progression and prevention and related mechanisms are still controversial. Our review depicts controversial activities for IL-33/ST2 within carcinogenesis and cancer prevention. Moreover, IL-33/ST2 signaling is a potential therapeutic target for CRC.

| S-EPMC8727260 | biostudies-literature

KCC2 overexpression prevents the paradoxical seizure-promoting action of somatic inhibition.

Project description:Although cortical interneurons are apparently well-placed to suppress seizures, several recent reports have highlighted a paradoxical role of perisomatic-targeting parvalbumin-positive (PV+) interneurons in ictogenesis. Here, we use an acute in vivo model of focal cortical seizures in awake behaving mice, together with closed-loop optogenetic manipulation of PV+ interneurons, to investigate their function during seizures. We show that photo-depolarization of PV+ interneurons rapidly switches from an anti-ictal to a pro-ictal effect within a few seconds of seizure initiation. The pro-ictal effect of delayed photostimulation of PV+ interneurons was not shared with dendrite-targeting somatostatin-positive (SOM+) interneurons. We also show that this switch can be prevented by overexpression of the neuronal potassium-chloride co-transporter KCC2 in principal cortical neurons. These results suggest that strategies aimed at improving the ability of principal neurons to maintain a trans-membrane chloride gradient in the face of excessive network activity can prevent interneurons from contributing to seizure perpetuation.

| S-EPMC6420604 | biostudies-literature

Overexpression of BIRC6 driven by EGF-JNK-HECTD1 signaling is a potential therapeutic target for triple-negative breast cancer.

Project description:Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease. The lack of targeted therapies and poor patient outcome have fostered efforts to discover new molecular targets to treat patients with TNBC. Here, we showed that baculoviral IAP repeat containing 6 (BIRC6) is overexpressed and positively correlated with epidermal growth factor (EGF) receptor (EGFR) in TNBC cells and tissues and that BIRC6 overexpression is associated with poor patient survival. Mechanistic studies revealed that BIRC6 stability is increased by EGF-JNK signaling, which prevents ubiquitination and degradation of BIRC6 mediated by the E3 ubiquitin ligase HECTD1. BIRC6 in turn decreases SMAC expression by inducing the ubiquitin-proteasome pathway, thereby antagonizing apoptosis and promoting the proliferation, colony formation, tumorsphere formation, and tumor growth capacity of TNBC cells. Therapeutically, the PEGylated cationic lipid nanoparticle (pCLN)-assisted delivery of BIRC6 small interfering RNA (siRNA) efficiently silences BIRC6 expression in TNBC cells, thus suppressing TNBC cell growth in vitro and in vivo, and its antitumor activity is significantly superior to that of the EGFR inhibitor gefitinib. Our findings identify an important regulatory mechanism of BIRC6 overexpression and provide a potential therapeutic option for treating TNBC.

| S-EPMC8526501 | biostudies-literature

Paradoxical overexpression of MBNL2 in hepatocellular carcinoma inhibits tumor growth and invasion.

Project description:Pre-mRNA alternative splicing is an essential step in the process of gene expression. It provides cells with the opportunity to create various protein isoforms. Disruptions of alternative splicing are associated with various diseases, including cancer. The muscleblind-like (MBNL) protein is a splicing regulatory protein. Overexpression of MBNL proteins in embryonic stem cells promotes differentiated cell-like alternative splicing patterns. We examined the expression level of MBNL2 in 143 resected HCCs using immunohistochemistry. MBNL2 was overexpressed in 51 (35.7%) HCCs. The overexpression of MBNL2 correlated with smaller tumor size (≤ 3 cm, P = 0.0108) and low tumor stage (Stage I, P = 0.0026), indicating that MBNL2 expression was lost in the late stage of HCC development. Furthermore, patients with MBNL2-positive HCCs had a borderline better 5-year overall survival (P = 0.0579). In non-cancerous liver parenchyma, MBNL2 was stained on the Canals of Hering and hepatocytes newly derived from hepatic progenitor cells. The overexpression of MBNL2 in Hep-J5 cells suppressed proliferation, tumorsphere formation, migration, and in vitro invasion, and also reduced in vivo tumor growth in NOD/SCID mice. In contrast, MBNL2 depletion with RNA interference in Huh7 cells increased in vitro migration and invasion, but did not enhance tumor growth. These results indicate that MBNL2 is a tumor suppressor in hepatocarcinogenesis.

| S-EPMC5323177 | biostudies-literature

Lipolysis-stimulated lipoprotein receptor overexpression is a novel predictor of poor clinical prognosis and a potential therapeutic target in gastric cancer.

Project description:The prognosis of patients with advanced gastric cancer (GC) remains poor despite the recent advances in molecular targeted therapies, and the search for biomarkers that can predict prognosis and additional new agents with acceptable toxicity profiles are needed. Lipolysis-stimulated lipoprotein receptor (LSR) is a lipoprotein receptor that binds to triglyceride-rich lipoproteins and related to some malignancies. Herein, we examined the association between LSR expression and the prognosis of patients with GC, and investigated the antitumor effect of a previously developed anti-human LSR monoclonal antibody (#1-25). We first performed immunohistochemical analysis of LSR protein expression in GC and normal tissues, and then examined its association with the prognosis of 110 patients with GC. LSR was overexpressed in most of primary GC and metastatic tumors, but not in normal tissues. Patients with strong LSR expression (N = 80, 72.7%) had significantly poorer overall survival (OS) than those with weak expression (P = 0.017). Multivariate analysis identified strong LSR (as well as pT) as independent and significant prognostic factors for OS. Next, we demonstrated that very low density lipoprotein (VLDL) treatment increases cell proliferation in LSR-expressing GC cell lines in vitro; LSR inhibition using #1-25 inhibited VLDL-induced proliferation by suppressing JAK/STAT and PI3K signaling. In vivo, we demonstrated a marked antitumor effect of #1-25 in 2 distinct GC cell line xenograft mice models. Our findings suggest that LSR plays a key functional role in GC development, and that this antigen can be therapeutically targeted to improve GC treatment.

| S-EPMC6152476 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data