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Calmodulin antagonist enhances DR5-mediated apoptotic signaling in TRA-8 resistant triple negative breast cancer cells.

ABSTRACT: Patients with triple negative breast cancer (TNBC) have no successful "targeted" treatment modality, which represents a priority for novel therapy strategies. Upregulated death receptor 5 (DR5) expression levels in breast cancer cells compared to normal cells enable TRA-8, a DR5 specific agonistic antibody, to specifically target malignant cells for apoptosis without inducing normal hepatocyte apoptosis. Drug resistance is a common obstacle in TRAIL-based therapy for TNBC. Calmodulin (CaM) is overexpressed in breast cancer. In this study, we characterized the novel function of CaM antagonist in enhancing TRA-8 induced cytotoxicity in TRA-8 resistant TNBC cells and its underlying molecular mechanisms. Results demonstrated that CaM antagonist(s) enhanced TRA-8 induced cytotoxicity in a concentration and time-dependent manner for TRA-8 resistant TNBC cells. CaM directly bound to DR5 in a Ca2+ dependent manner, and CaM siRNA promoted DR5 recruitment of FADD and caspase-8 for DISC formation and TRA-8 activated caspase cleavage for apoptosis in TRA-8 resistant TNBC cells. CaM antagonist, trifluoperazine, enhanced TRA-8 activated DR5 oligomerization, DR5-mediated DISC formation, and TRA-8 activated caspase cleavage for apoptosis, and decreased anti-apoptotic pERK, pAKT, XIAP, and cIAP-1 expression in TRA-8 resistant TNBC cells. These results suggest that CaM could be a key regulator to mediate DR5-mediated apoptotic signaling, and suggests a potential strategy for using CaM antagonists to overcome drug resistance of TRAIL-based therapy for TRA-8 resistant TNBC.

SUBMITTER: Fancy RM

PROVIDER: S-EPMC5993614 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Calmodulin antagonist enhances DR5-mediated apoptotic signaling in TRA-8 resistant triple negative breast cancer cells.

Fancy Romone M RM Kim Harrison H Napier Tiara T Buchsbaum Donald J DJ Zinn Kurt R KR Song Yuhua Y

Journal of cellular biochemistry 20180416 7

Patients with triple negative breast cancer (TNBC) have no successful "targeted" treatment modality, which represents a priority for novel therapy strategies. Upregulated death receptor 5 (DR5) expression levels in breast cancer cells compared to normal cells enable TRA-8, a DR5 specific agonistic antibody, to specifically target malignant cells for apoptosis without inducing normal hepatocyte apoptosis. Drug resistance is a common obstacle in TRAIL-based therapy for TNBC. Calmodulin (CaM) is ov ...[more]

PMID: 29663486

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Project description:Background/aimCompared to other breast cancer types, triple-negative breast cancer (TNBC) has historically had few treatment alternatives. Therefore, exploring and pinpointing potentially implicated genes could be used for treating and managing TNBC. By doing this, we will provide essential data to comprehend how the genes are involved in the apoptotic pathways of the cancer cells to identify potential therapeutic targets. Analysis of a single genetic alteration may not reveal the pathogenicity driving TNBC due to the high genomic complexity and heterogeneity of TNBC. Therefore, searching through a large variety of gene interactions enabled the identification of molecular therapeutic genes.Materials and methodsThis study used integrated bioinformatics methods such as UALCAN, TNM plotter, PANTHER, GO-KEEG and PPIs to assess the gene expression, protein-protein interaction (PPI), and transcription factor interaction of apoptosis-regulated genes.ResultsCompared to normal breast tissue, gene expressions of BNIP3, TNFRSF10B, MCL1, and CASP4 were downregulated in UALCAN. At the same time, BIK, AKT1, BAD, FADD, DIABLO, and CASP9 was down-regulated in bc-GeneExMiner v4.5 mRNA expression (BCGM) databases. Based on GO term enrichment analysis, the cellular process (GO:0009987), which has about 21 apoptosis-regulated genes, is the top category in the biological processes (BP), followed by biological regulation (GO:0065007). We identified 29 differentially regulated pathways, including the p53 pathway, angiogenesis, apoptosis signaling pathway, and the Alzheimer's disease presenilin pathway. We examined the PPIs between the genes that regulate apoptosis; CASP3 and CASP9 interact with FADD, MCL1, TNF, TNFRSRF10A, and TNFRSF10; additionally, CASP3 significantly forms PPIs with CASP9, DFFA, and TP53, and CASP9 with DIABLO. In the top 10 transcription factors, the androgen receptor (AR) interacts with five apoptosis-regulated genes (p<0.0001; q<0.01), followed by retinoic acid receptor alpha (RARA) (p<0.0001; q<0.01) and ring finger protein (RNF2) (p<0.0001; q<0.01). Overall, the gene expression profile, PPIs, and the apoptosis-TF interaction findings suggest that the 27 apoptosis-regulated genes might be used as promising targets in treating and managing TNBC. Furthermore, from a total of 27 key genes, CASP2, CASP3, DAPK1, TNF, TRAF2, and TRAF3 were significantly correlated with poor overall survival in TNBC (p-value <0.05); they could play important roles in the progression of TNBC and provide attractive therapeutic targets that may offer new candidate molecules for targeted therapy.ConclusionOur findings demonstrate that CASP2, CASP3, DAPK1, TNF, TRAF2, and TRAF3 were substantially associated with the overall survival rate (OS) difference of TNBC patients out of a total of 27 specific genes used in this study, which may play crucial roles in the development of TNBC and offer promising therapeutic interventions.

Project description:BACKGROUND:Understanding mechanisms underlying specific chemotherapeutic responses in subtypes of cancer may improve identification of treatment strategies most likely to benefit particular patients. For example, triple-negative breast cancer (TNBC) patients have variable response to the chemotherapeutic agent cisplatin. Understanding the basis of treatment response in cancer subtypes will lead to more informed decisions about selection of treatment strategies. METHODS:In this study we used an integrative functional genomics approach to investigate the molecular mechanisms underlying known cisplatin-response differences among subtypes of TNBC. To identify changes in gene expression that could explain mechanisms of resistance, we examined 102 evolutionarily conserved cisplatin-associated genes, evaluating their differential expression in the cisplatin-sensitive, basal-like 1 (BL1) and basal-like 2 (BL2) subtypes, and the two cisplatin-resistant, luminal androgen receptor (LAR) and mesenchymal (M) subtypes of TNBC. RESULTS:We found 20 genes that were differentially expressed in at least one subtype. Fifteen of the 20 genes are associated with cell death and are distributed among all TNBC subtypes. The less cisplatin-responsive LAR and M TNBC subtypes show different regulation of 13 genes compared to the more sensitive BL1 and BL2 subtypes. These 13 genes identify a variety of cisplatin-resistance mechanisms including increased transport and detoxification of cisplatin, and mis-regulation of the epithelial to mesenchymal transition. CONCLUSIONS:We identified gene signatures in resistant TNBC subtypes indicative of mechanisms of cisplatin. Our results indicate that response to cisplatin in TNBC has a complex foundation based on impact of treatment on distinct cellular pathways. We find that examination of expression data in the context of heterogeneous data such as drug-gene interactions leads to a better understanding of mechanisms at work in cancer therapy response.

Dataset Information

Calmodulin antagonist enhances DR5-mediated apoptotic signaling in TRA-8 resistant triple negative breast cancer cells.

Publications

Calmodulin antagonist enhances DR5-mediated apoptotic signaling in TRA-8 resistant triple negative breast cancer cells.

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