Autophagy-Mediated Clearance of Free Genomic DNA in the Cytoplasm Protects the Growth and Survival of Cancer Cells

Abstract

The cGAS (GMP-AMP synthase)-mediated senescence-associated secretory phenotype (SASP) and DNA-induced autophagy (DNA autophagy) have been extensively investigated in recent years. However, cGAS-mediated autophagy has not been elucidated in cancer cells. The described investigation revealed that active DNA autophagy but not SASP activity could be detected in the BT-549 breast cancer cell line with high micronucleus (MN) formation. DNA autophagy was identified as selective autophagy of free genomic DNA in the cytoplasm but not nucleophagy. The process of DNA autophagy in the cytosol could be initiate by cGAS and usually cooperates with SQSTM1-mediated autophagy of ubiquitinated histones. Cytoplasmic DNA, together with nuclear proteins such as histones, could be derived from DNA replication-induced nuclear damage and MN collapse. The inhibition of autophagy through chemical inhibitors as well as the genomic silencing of cGAS or SQSTM1 could suppress the growth and survival of cancer cells, and induced DNA damage could increase the sensitivity to these inhibitors. Furthermore, expanded observations of several other kinds of human cancer cells indicated that high relative DNA autophagy or enhancement of DNA damage could also increase or sensitize these cells to inhibition of DNA autophagy.

cGAS regulates the DNA damage response to maintain proliferative signaling in gastric cancer cells

“…As assumed, the silencing of cGAS led to decreased cells proliferation, migration, and increased apoptosis in AGS and MKN45 cells. Previously, it has been reported that silencing cGAS decrease the viability of BT-549 cells [34]; furthermore, our xenograft experiment in BALB/nu mice also demonstrated a decrease in tumor growth in sh-cGAS MKN45 cells. To explore how cGAS exert the proliferation of GC cells, we performed GO and KEGG functional enrichment analysis, which showed its involvement in DNA replication and repair.…”

Expression of SASP, DNA Damage Response, and Cell Proliferation Factors in Early Gastric Neoplastic Lesions: Correlations and Clinical Significance

“…Nevertheless, the progression of cancers is a complicated process, collectively determined by various factors that are interactively fabricated in cancer cells and tumour microenvironments. More interestingly, our recent investigation revealed that cGAS-STING could be activated in severe DNA damage; however, SASP activity has been shown to alternatively mediate DNA autophagy in protecting cancer cell survival [37]. In fact, STAT6 expression is also positively and negatively involved in cancer progression [38].…”

H-151, a Selective STING Inhibitor, Has Potential as a Treatment for Neovascular Age-Related Macular Degeneration

“…Notably, the cellular senescent phenotype is inhibited by H-151 treatment. 25 , 33 A recent study showed that systemic H-151 administration can alleviate inflammatory diseases, including acute kidney injury, 34 neuron loss, and neurologic disability in amyotrophic lateral sclerosis model mice. 21 These data suggested that H-151 is a promising therapeutic agent for inflammatory disorders.…”