β-adrenergic receptor inhibition enhances oncolytic herpes virus propagation through STAT3 activation in gastric cancer

Jiali Hu; Ruitao Lu; Yu Zhang; Wei Li; Qian Hu; Cuiyu Chen; Zhaoqian Liu; Wei Zhang; Ling Chen; Ran Xu; Jia Luo; Howard L McLeod; Yijing He

doi:10.1186/s13578-021-00687-1

β-adrenergic receptor inhibition enhances oncolytic herpes virus propagation through STAT3 activation in gastric cancer

Cell Biosci. 2021 Sep 20;11(1):174. doi: 10.1186/s13578-021-00687-1.

Authors

Jiali Hu^#^{1

2

3

4}, Ruitao Lu^#⁵, Yu Zhang^{1

2

3}, Wei Li^{1

2

3}, Qian Hu^{1

2

3}, Cuiyu Chen^{1

2

3}, Zhaoqian Liu^{1

2

3}, Wei Zhang^{1

2

3}, Ling Chen⁶, Ran Xu⁷, Jia Luo⁸, Howard L McLeod^{1

2

9}, Yijing He^{10

11

12}

Affiliations

¹ Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410000, Hunan, China.
² Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, Hunan, China.
³ National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁴ Zhuhai People's Hospital (Zhuhai Hospital Affiliated With Jinan University), Zhuhai, Guangdong, China.
⁵ School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
⁶ Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
⁷ Department of Urology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
⁸ Department of Hepatobiliary and Intestinal Surgery, Hunan Cancer Hospital, Changsha, Hunan, China.
⁹ Geriatric Oncology Consortium, Tampa, FL, USA.
¹⁰ Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410000, Hunan, China. heyijing@csu.edu.cn.
¹¹ Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, Hunan, China. heyijing@csu.edu.cn.
¹² National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. heyijing@csu.edu.cn.

^# Contributed equally.

Abstract

Background: Oncolytic viruses (OVs) are considered a promising therapeutic alternative for cancer. However, OVs could activate the host innate immunity, then impair the viral propagation in tumor cells. In this study, we explored the effect of propranolol, a non-selective β-blocker, on the antitumor efficacy of T1012G virus in gastric cancer models.

Methods: The proliferation of gastric cancer cells treated with monotherapy or combination treatment was detected by CCK8 cell proliferation assay. The effect of propranolol was further evaluated by in vitro viral replication assays. In vivo tumor xenograft experiments were used to observe the effect of combination therapy on gastric cancer growth in mice. The expression levels of viral proteins and interferon responsive genes were detected in the gastric cancer cell lines treated with combined treatment by western blot. The impact of propranolol on IFN-α/β-mediated inhibition of viral propagation and the expression of antiviral gene PKR was detected by viral replication assays and western blot.

Results: Cell viability assay detected a 97.9% decrease of T1012G IC50 in HGC-27 when it was pretreated with propranolol along with a sevenfold increase of virus titers compared with T1012G only group (P < 0.001). Moreover, propranolol pretreatment caused sustained tumor regression (335.3 ± 36.92 mm³ vs. 1118 ± 210.0 mm³, P < 0.01) and enhanced the viral propagation (fourfold increase, P < 0.01) compared with T1012G only group. Propranolol pretreatment significantly enhanced the p-STAT3 (2.9-fold, P < 0.05) and suppressed p-PKR (65.94% ± 10.11%, P < 0.05) compared with T1012G only group. In addition, propranolol could counteract IFN-α/β-mediated inhibition of viral propagation (compared with IFNα: 5.1-fold, P < 0.001; IFNβ: 4.6-fold, P < 0.01) or enhancement of PKR activation (IFNα: 92.57% ± 1.77%, P < 0.001, IFNβ: 99.34% ± 0.13% decrease, P < 0.001).

Conclusions: In summary, β-blocker pretreatment could improve the propagation and therapeutic efficacy of T1012G in human gastric cancer by regulating STAT3-PKR signaling cascade, even in the presence of type I IFNs. These data support new strategies of improving the efficacy of OVs in gastric cancer.

Keywords: Gastric cancer; Innate immunity; Oncolytic virus; Propranolol; Type I IFN signaling.

Abstract

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