journal contribution posted on 2023-03-31, 03:07 authored by Diana Rose E. Ranoa, Ryan C. Widau, Stephen Mallon, Akash D. Parekh, Claudia M. Nicolae, Xiaona Huang, Michael J. Bolt, Ainhoa Arina, Renate Parry, Stephen J. Kron, George-Lucian Moldovan, Nikolai N. Khodarev, Ralph R. Weichselbaum
(A) Quantification of bands from Western gel shown in Main Figure 3A using Image J. The pixel units obtained for each protein band was normalized to the pixel units calculated from their respective b-Actin loading control. (B-G) Clonogenic survival of various human and mice tumor cell lines with stable shSTING knockdown in response to increasing dose of IR. (H-I) Cell viability assays of primary and immortalized MEFs isolated from WT and STING-/- mice in response to increasing IR dose. Data are representative of at least three experiments. P-values were determined using unpaired Student's t-test. Error bars are SEM. *P < 0.05, **P < 0.01, ***P < 0.005.
Ludwig Center for Metastasis Research
Virginia and Ludwig Foundation for Cancer Research
Lung Cancer Research Foundation
ARTICLE ABSTRACTGiven the integral role of stimulator of interferon genes (STING, TMEM173) in the innate immune response, its loss or impairment in cancer is thought to primarily affect antitumor immunity. Here we demonstrate a role for STING in the maintenance of cellular homeostasis through regulation of the cell cycle. Depletion of STING in human and murine cancer cells and tumors resulted in increased proliferation compared with wild-type controls. Microarray analysis revealed genes involved in cell-cycle regulation are differentially expressed in STINGko compared with WT MEFs. STING-mediated regulation of the cell cycle converged on NFκB- and p53-driven activation of p21. The absence of STING led to premature activation of cyclin-dependent kinase 1 (CDK1), early onset to S-phase and mitosis, and increased chromosome instability, which was enhanced by ionizing radiation. These results suggest a pivotal role for STING in maintaining cellular homeostasis and response to genotoxic stress.
These findings provide clear mechanistic understanding of the role of STING in cell-cycle regulation, which may be exploited in cancer therapy because most normal cells express STING, while many tumor cells do not.See related commentary by Gius and Zhu, p. 1295