The analog of cGAMP, c-di-AMP, activates STING mediated cell death pathway in estrogen-receptor negative breast cancer cells
- Resource Type
- Authors
- Minal Mane; Hitesh Vasiyani; Rajesh Singh; Kritarth Singh; Jyoti Singh; Fatema Currim; Anjali Shinde; Milton Roy; Dhruv Gohel; Mahesh Chhabria; Khushali Vaidya
- Source
- Apoptosis. 26:293-306
- Subject
- 0301 basic medicine
Cancer Research
Programmed cell death
Clinical Biochemistry
Pharmaceutical Science
Apoptosis
Triple Negative Breast Neoplasms
medicine.disease_cause
Metastasis
03 medical and health sciences
0302 clinical medicine
Immune system
Cell Line, Tumor
medicine
Humans
Pharmacology
Tumor microenvironment
Innate immune system
Cell Death
Chemistry
Biochemistry (medical)
Membrane Proteins
Cell Biology
medicine.disease
Immunity, Innate
eye diseases
Mitochondria
Sting
030104 developmental biology
Receptors, Estrogen
030220 oncology & carcinogenesis
Interferon Type I
Cancer research
Interferon Regulatory Factor-3
Receptors, Progesterone
Carcinogenesis
Dinucleoside Phosphates
Protein Binding
Signal Transduction
- Language
- ISSN
- 1573-675X
1360-8185
Immune adaptor protein like STING/MITA regulate innate immune response and plays a critical role in inflammation in the tumor microenvironment and regulation of metastasis including breast cancer. Chromosomal instability in highly metastatic cells releases fragmented chromosomal parts in the cytoplasm, hence the activation of STING via an increased level of cyclic dinucleotides (cDNs) synthesized by cGMP-AMP synthase (cGAS). Cyclic dinucleotides 2' 3'-cGAMP and it's analog can potentially activate STING mediated pathways leading to nuclear translocation of p65 and IRF-3 and transcription of inflammatory genes. The differential modulation of STING pathway via 2' 3'-cGAMP and its analog and its implication in breast tumorigenesis is still not well explored. In the current study, we demonstrated that c-di-AMP can activate type-1 IFN response in ER negative breast cancer cell lines which correlate with STING expression. c-di-AMP binds to STING and activates downstream IFN pathways in STING positive metastatic MDA-MB-231/MX-1 cells. Prolonged treatment of c-di-AMP induces cell death in STING positive metastatic MDA-MB-231/MX-1 cells mediated by IRF-3. c-di-AMP induces IRF-3 translocation to mitochondria and initiates Caspase-9 mediated cell death and inhibits clonogenicity of triple-negative breast cancer cells. This study suggests that c-di-AMP can activate and modulates STING pathway to induce mitochondrial mediated apoptosis in estrogen-receptor negative breast cancer cells.