STING promotes homeostasis via regulation of cell proliferation and chromosomal stability

Diana Rose E. Ranoa, Ryan C. Widau, Stephen Mallon, Akash D. Parekh, Claudia Nicolae, Xiaona Huang, Michael J. Bolt, Ainhoa Arina, Renate Parry, Stephen J. Kron, George-Lucian Moldovan, Nikolai N. Khodarev, Ralph R. Weichselbaum

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Given 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 NFkB- 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. Significance: 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.

Original languageEnglish (US)
Pages (from-to)1465-1479
Number of pages15
JournalCancer Research
Volume79
Issue number7
DOIs
StatePublished - Apr 1 2019

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Chromosomal Instability
Homeostasis
Cell Proliferation
Cell Cycle
Neoplasms
CDC2 Protein Kinase
Microarray Analysis
Ionizing Radiation
S Phase
Mitosis
Innate Immunity
Interferons
Genes
DNA Damage
Immunity
Maintenance

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Ranoa, D. R. E., Widau, R. C., Mallon, S., Parekh, A. D., Nicolae, C., Huang, X., ... Weichselbaum, R. R. (2019). STING promotes homeostasis via regulation of cell proliferation and chromosomal stability. Cancer Research, 79(7), 1465-1479. https://doi.org/10.1158/0008-5472.CAN-18-1972
Ranoa, Diana Rose E. ; Widau, Ryan C. ; Mallon, Stephen ; Parekh, Akash D. ; Nicolae, Claudia ; Huang, Xiaona ; Bolt, Michael J. ; Arina, Ainhoa ; Parry, Renate ; Kron, Stephen J. ; Moldovan, George-Lucian ; Khodarev, Nikolai N. ; Weichselbaum, Ralph R. / STING promotes homeostasis via regulation of cell proliferation and chromosomal stability. In: Cancer Research. 2019 ; Vol. 79, No. 7. pp. 1465-1479.
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abstract = "Given 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 NFkB- 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. Significance: 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.",
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Ranoa, DRE, Widau, RC, Mallon, S, Parekh, AD, Nicolae, C, Huang, X, Bolt, MJ, Arina, A, Parry, R, Kron, SJ, Moldovan, G-L, Khodarev, NN & Weichselbaum, RR 2019, 'STING promotes homeostasis via regulation of cell proliferation and chromosomal stability', Cancer Research, vol. 79, no. 7, pp. 1465-1479. https://doi.org/10.1158/0008-5472.CAN-18-1972

STING promotes homeostasis via regulation of cell proliferation and chromosomal stability. / Ranoa, Diana Rose E.; Widau, Ryan C.; Mallon, Stephen; Parekh, Akash D.; Nicolae, Claudia; Huang, Xiaona; Bolt, Michael J.; Arina, Ainhoa; Parry, Renate; Kron, Stephen J.; Moldovan, George-Lucian; Khodarev, Nikolai N.; Weichselbaum, Ralph R.

In: Cancer Research, Vol. 79, No. 7, 01.04.2019, p. 1465-1479.

Research output: Contribution to journalArticle

TY - JOUR

T1 - STING promotes homeostasis via regulation of cell proliferation and chromosomal stability

AU - Ranoa, Diana Rose E.

AU - Widau, Ryan C.

AU - Mallon, Stephen

AU - Parekh, Akash D.

AU - Nicolae, Claudia

AU - Huang, Xiaona

AU - Bolt, Michael J.

AU - Arina, Ainhoa

AU - Parry, Renate

AU - Kron, Stephen J.

AU - Moldovan, George-Lucian

AU - Khodarev, Nikolai N.

AU - Weichselbaum, Ralph R.

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Given 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 NFkB- 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. Significance: 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.

AB - Given 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 NFkB- 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. Significance: 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.

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U2 - 10.1158/0008-5472.CAN-18-1972

DO - 10.1158/0008-5472.CAN-18-1972

M3 - Article

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JF - Cancer Research

SN - 0008-5472

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