STING Promotes Breast Cancer Cell Survival by an Inflammatory-Independent Nuclear Pathway Enhancing the DNA Damage Response

AbstractSTING (Stimulator of Interferon Genes) is a well-known endoplasmic reticulum-anchored adaptor of the innate immunity that triggers the expression of inflammatory cytokines in response to pathogen infection. In cancer cells, this pro-inflammatory pathway can be activated by genomic DNA damage potentiating antitumor immune responses. Here we report that STING promotes cancer cell survival and resistance to genotoxic treatment in a cell-autonomous manner. Mechanistically, we show that STING partly localizes at the inner nuclear membrane in various breast cancer cell lines and clinical tumor samples, and interacts with several proteins of the DNA damage response (DDR). STING overexpression enhances the amount of chromatin-bound DNA-dependent Protein Kinase (DNA-PK) complex, while STING silencing impairs DDR foci formation and DNA repair efficacy. Importantly, this function of STING is independent of its canonical pro-inflammatory pathway. This study highlights a previously unappreciated cell-autonomous tumor-promoting mechanism of STING that opposes its well-documented role in tumor immunosurveillance.Graphical abstract

Download Full-text

miR-302b enhances breast cancer cell sensitivity to cisplatin by regulating E2F1 and the cellular DNA damage response

Oncotarget ◽

10.18632/oncotarget.6381 ◽

2015 ◽

Vol 7 (1) ◽

pp. 786-797 ◽

Cited By ~ 36

Author(s):

Alessandra Cataldo ◽

Douglas G. Cheung ◽

Andrea Balsari ◽

Elda Tagliabue ◽

Vincenzo Coppola ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Dna Damage Response ◽

Cell Sensitivity ◽

Damage Response ◽

Cellular Dna

Download Full-text

mTORC1 and -2 Coordinate Transcriptional and Translational Reprogramming in Resistance to DNA Damage and Replicative Stress in Breast Cancer Cells

Molecular and Cellular Biology ◽

10.1128/mcb.00577-16 ◽

2016 ◽

Vol 37 (5) ◽

Cited By ~ 15

Author(s):

Deborah Silvera ◽

Amanda Ernlund ◽

Rezina Arju ◽

Eileen Connolly ◽

Viviana Volta ◽

...

Keyword(s):

Dna Damage ◽

Dna Replication ◽

Cell Survival ◽

Cancer Cell ◽

Dna Damage Response ◽

Translational Regulation ◽

Tumor Control ◽

Replicative Stress ◽

Damage Response ◽

Cancer Cell Survival

ABSTRACT mTOR coordinates growth signals with metabolic pathways and protein synthesis and is hyperactivated in many human cancers. mTOR exists in two complexes: mTORC1, which stimulates protein, lipid, and ribosome biosynthesis, and mTORC2, which regulates cytoskeleton functions. While mTOR is known to be involved in the DNA damage response, little is actually known regarding the functions of mTORC1 compared to mTORC2 in this regard or the respective impacts on transcriptional versus translational regulation. We show that mTORC1 and mTORC2 are both required to enact DNA damage repair and cell survival, resulting in increased cancer cell survival during DNA damage. Together mTORC1 and -2 enact coordinated transcription and translation of protective cell cycle and DNA replication, recombination, and repair genes. This coordinated transcriptional-translational response to DNA damage was not impaired by rapalog inhibition of mTORC1 or independent inhibition of mTORC1 or mTORC2 but was blocked by inhibition of mTORC1/2. Only mTORC1/2 inhibition reversed cancer cell resistance to DNA damage and replicative stress and increased tumor cell killing and tumor control by DNA damage therapies in animal models. When combined with DNA damage, inhibition of mTORC1/2 blocked transcriptional induction more strongly than translation of DNA replication, survival, and DNA damage response mRNAs.

Download Full-text