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Forskolin Enhances Antitumor Effect of Oncolytic Measles Virus by Promoting Rab27a Dependent Vesicular Transport System

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Abstract

The measles vaccine virus strain (MV-Edm) serves as a potential platform for the development of effective oncolytic vectors. Nevertheless, despite promising pre-clinical data, our comprehension of the factors influencing the efficacy of MV-Edm infection and intratumoral spread, as well as the interactions between oncolytic viruses and specific chemotherapeutics associated with viral infection, remains limited. Therefore, we investigated the potency of Forskolin in enhancing the antitumor effect of oncolytic MV-Edm by promoting the Rab27a-dependent vesicular transport system. After infecting cells with MV-Edm, we observed an increased accumulation of cytoplasmic vesicles. Our study demonstrated that MV-Edm infection and spread in tumors, which are indispensable processes for viral oncolysis, depend on the vesicular transport system of tumor cells. Although tumor cells displayed a responsive mechanism to restrain the MV-Edm spread by down-regulating the expression of Rab27a, a key member of the vesicle transport system, over-expression of Rab27a promoted the oncolytic efficacy of MV-Edm towards A549 tumor cells. Additionally, we found that Forskolin, a Rab27a agonist, was capable of promoting the oncolytic effect of MV-Edm in vitro. Our study revealed that the vesicle transporter Rab27a could facilitate the secretion of MV-Edm and the generation of syncytial bodies in MV-Edm infected cells during the MV-Edm-mediated oncolysis pathway. The results of the study demonstrate that a combination of Forskolin and MV-Edm exerts a synergistic anti-tumor effect in vitro, leading to elevated oncolysis. This finding holds promise for the clinical treatment of patients with tumors.

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Abbreviations

DMEM:

Dulbecco’s modified eagle medium

MV-Edm:

Attenuated measles virus of the Edmonston strain

PBS:

Phosphate-buffered saline

RT-PCR:

Reverse transcription polymerase chain reaction

TCID50:

Tissue culture infective dose

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Funding

This project was supported by the National Natural Science Foundation of China (82073367 and 81903147), Medical School of Nanjing University (2022-LCYJ-MS-28) and Medical School of Nanjing University (2022-LCYJ-PY-20).

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Author notes

  1. Mao Xia and Yangbin Wang have equally contributed to this work.

Authors and Affiliations

  1. Department of Laboratory Medicine, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China

    Mao Xia, Yangbin Wang & Yongquan Xia

  2. Medical Laboratory of Taizhou Fourth People’s Hospital, Taizhou, 225300, China

    Jiawei Zeng

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  1. Mao Xia
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Contributions

Conception and design: Jiawei Zeng and Mao Xia. Development of methodology: Mao Xia and Yangbin Wang. Acquisition of data (provided animals, provided facilities, etc.): Mao Xia, Yangbin Wang and Yongquan Xia. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): Xia M, Yangbin Wang. Writing, review, and/or revision of the manuscript: Mao Xia and Yongquan Xia. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): Jiawei Zeng, Xia M and Yongquan Xia. Study supervision: Jiawei Zeng. All authors read and approved the final manuscript.

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Correspondence to Jiawei Zeng.

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The protocol of this study was approved by the Research Ethics Committee of the Medical School of Nanjing University. The experiments were carried out in accordance with approved guidelines and regulations.

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Xia, M., Wang, Y., Xia, Y. et al. Forskolin Enhances Antitumor Effect of Oncolytic Measles Virus by Promoting Rab27a Dependent Vesicular Transport System. Curr Microbiol 81, 93 (2024). https://doi.org/10.1007/s00284-024-03613-z

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