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Dissecting the role of cell signaling versus CD8+ T cell modulation in propranolol antitumor activity

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Abstract

Preclinical and early clinical mechanistic studies of antitumor activity from the beta-adrenergic receptor (β-AR) blocker propranolol have revealed both cell signaling and immune function pathway effects. Intertumoral studies were performed using propranolol, a β1-AR selective agent (atenolol), and a β2-AR selective agent (ICI 118,551) in a preclinical in vivo model, as a step to dissect the contribution of cell signaling and CD8+ immunological effects on anticancer activity. We found that repression of β2-AR but not β1-AR signaling selectively suppressed cell viability and inhibited xenograft growth in vivo. Moreover, western blot analysis indicated that the phosphorylation levels of AKT/MEK/ERK were significantly decreased following the inhibition of β2-AR. Furthermore, propranolol was found to activate the tumor microenvironment by inducing an increased intratumoral frequency of CD8+ T cells, whereas neither selective β1 nor β2-AR blockers had a significant effect on the tumor immune microenvironment. Thus, the results of this mechanistic dissection support a predominant role of tumor cell signaling, rather than the accumulation of CD8+ T cells, as the basis for propranolol antitumor activity.

Key messages

  • Molecular signaling of AKT/MAPK pathway contributes to propranolol caused cancer control.

  • CD8+ T cells in tumor microenvironment were activated upon propranolol exposure.

  • The basis for propranolol antitumor activity was predominantly dependent on cell signaling, rather than the activation of CD8+ T cells.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This manuscript is dedicated to the memory of our collaborator Sanjiv Sam Gambhir, whose death inspires us. “and yet, we try”.

Funding

This study was supported by the National Natural Science Foundation of China (No. 82173906); the key project of Ministry of Science and Technology, China (2022YFC2010004); Chinese National Major Project for New Drug Innovation. (No. 2019ZX09201-002-006); the key project of Health Commission of Hunan Province (No.202113010141); Natural Science Foundation of Hunan Province, China (No.2021JJ31063 and No.2021JJ31044). Fundamental Research Funds for the Central Universities of Central South University (No.198101066 and No.208111176).

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008, People’s Republic of China

    Wei Li, Jielin Wan, Cuiyu Chen, Chengfang Zhou, Ping Liao, Qian Hu, Jiali Hu, Yang Wang, Yu Zhang, Yuanfei Huang, Weihua Huang, Wei Zhang, Howard L. Mcleod & Yijing He

  2. Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, 110 Xiangya Road, Changsha, 410078, People’s Republic of China

    Wei Li, Jielin Wan, Cuiyu Chen, Chengfang Zhou, Ping Liao, Qian Hu, Jiali Hu, Yang Wang, Yu Zhang, Yuanfei Huang, Weihua Huang, Wei Zhang & Yijing He

  3. Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, 110 Xiangya Road, Changsha, 410078, People’s Republic of China

    Wei Li, Jielin Wan, Cuiyu Chen, Chengfang Zhou, Ping Liao, Qian Hu, Jiali Hu, Yang Wang, Yu Zhang, Yuanfei Huang, Weihua Huang, Wei Zhang & Yijing He

  4. Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China

    Cong Peng

  5. National Clinical Research Center for Geriatric Disorders, 87 Xiangya Road, Changsha, Hunan, 410008, People’s Republic of China

    Yuanfei Huang, Weihua Huang, Wei Zhang & Yijing He

  6. Intermountain Precision Genomics, Intermountain Healthcare, St. George, UT, 84770, USA

    Howard L. Mcleod

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  1. Wei Li
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Correspondence to Howard L. Mcleod or Yijing He.

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Prof McLeod is on the board of directors for Vyant Bio. He is one of the founders of Interpares Biomedicine and Clariifi and a consultant to Pharmazam and eviCORE Health Solutions. All other authors declared no competing interests for this work.

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Wei Li and Jielin Wan contributed equally to this work.

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Li, W., Wan, J., Chen, C. et al. Dissecting the role of cell signaling versus CD8+ T cell modulation in propranolol antitumor activity. J Mol Med 100, 1299–1306 (2022). https://doi.org/10.1007/s00109-022-02238-8

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  • DOI: https://doi.org/10.1007/s00109-022-02238-8

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