title: Activation of Cyclic Adenosine Monophosphate Pathway Increases the Sensitivity of Cancer Cells to the Oncolytic Virus M1.
abstract: Oncolytic virotherapy is a novel and emerging treatment modality that uses replication-competent viruses to destroy cancer cells. Although diverse cancer cell types are sensitive to oncolytic viruses, one of the major challenges of oncolytic virotherapy is that the sensitivity to oncolysis ranges among different cancer cell types. Furthermore, the underlying mechanism of action is not fully understood. Here, we report that activation of cyclic adenosine monophosphate (cAMP) signaling significantly sensitizes refractory cancer cells to alphavirus M1 in vitro, in vivo, and ex vivo. We find that activation of the cAMP signaling pathway inhibits M1-induced expression of antiviral factors in refractory cancer cells, leading to prolonged and severe endoplasmic reticulum (ER) stress, and cell apoptosis. We also demonstrate that M1-mediated oncolysis, which is enhanced by cAMP signaling, involves the factor, exchange protein directly activated by cAMP 1 (Epac1), but not the classical cAMP-dependent protein kinase A (PKA). Taken together, cAMP/Epac1 signaling pathway activation inhibits antiviral factors and improves responsiveness of refractory cancer cells to M1-mediated virotherapy.
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Haipeng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Urology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Jianguang
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jiankai
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.affiliation: State Key Laboratory for Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Liwu
authors.initials: L
authors.lastname: Fu
authors.affiliation: State Key Laboratory for Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Cai
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yaqian
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yin
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Bingzheng
authors.initials: B
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Xing
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Lipeng
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jialuo
authors.initials: J
authors.lastname: Mai
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Wenli
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Pengxin
authors.initials: P
authors.lastname: Qiu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xingwen
authors.initials: X
authors.lastname: Su
authors.affiliation: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Microbiology and Physiology Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.affiliation: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.|Department of Microbiology and Physiology Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Phillip W L
authors.initials: PW
authors.lastname: Tai
authors.affiliation: Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Guangmei
authors.initials: G
authors.lastname: Yan
mesh_terms: D000524:Alphavirus / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D005576:Colforsin / Q000008:administration & dosage* / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D005576:Colforsin; D000242:Cyclic AMP