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J Cell Biochem. 2018 Jul;119(7):6216-6230. doi: 10.1002/jcb.26848. Epub 2018 Apr 16.

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

Author information

1
Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, Alabama.
2
Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama.
3
Hospital, University of Alabama at Birmingham, Birmingham, Alabama.
4
Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
5
Department of Radiology and Biomedical Engineering, Michigan State University, East Lansing, Michigan.

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.

KEYWORDS:

DISC; DR5 oligomerization; TRA-8 resistant TNBC cells; apoptosis; calmodulin antagonist; death receptor 5

PMID:
29663486
PMCID:
PMC5993614
[Available on 2019-07-01]
DOI:
10.1002/jcb.26848
[Indexed for MEDLINE]

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