Autophagy promotes oncolysis of an adenovirus expressing apoptin in human bladder cancer models

Summary

As a potential cancer therapy, we developed a recombinant adenovirus named Ad-VT, which was designed to express the apoptosis-inducing gene (apoptin) and selectively replicate in cancer cells via E1a manipulation. However, how it performs in bladder cancer remains unclear. We examined the antitumor efficacy of Ad-VT in bladder cancers using CCK-8 assays and xenograft models. Autophagy levels were evaluated by western blotting, MDC staining, and RFP-GFP-LC3 aggregates’ analyses. Here, we report the selective replication and antitumor efficacy (viability inhibition and apoptosis induction) of Ad-VT in bladder cancer cells. Using xenograft tumor models, we demonstrate that its effects are tumor specific resulting in the inhibition of tumor growth and improvement of the survival of mice models. Most Importantly, Ad-VT induced a complete autophagy flux leading to autophagic cancer cell death through a signaling pathway involving AMPK, raptor and mTOR. Finally, we suggest that treatment combination of Ad-VT and rapamycin results in a synergistic improvement of tumor control and survival compared to monotherapy. This study suggests that Ad-VT can induce selective autophagic antitumor activities in bladder cancer through the AMPK-Raptor-mTOR pathway, which can be further improved by rapamycin.

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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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Funding

This work was supported by the Key projects of science and technology boosting economy in 2020, (grant number SQ2020YFF0417940).

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Authors

Contributions

Chao Shang conceived and performed the experiments and analysed the data. Chen-Chen Ge, Jing Lu, Gao-Jie Song, Yi-Long Zhu, Yi-Quan Li, Zhi-Ru Xiu, Wen-Jie Li, Shan-Zhi Li, Jia-Nan Cong, Zi-Rui Liu conducted the mouse experiments. Li Xiao, Li-Li Sun and Ning-Yi Jin overall supervised the experiments and revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xiao Li or Li-Li Sun or Ning-Yi Jin.

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The authors declare that they have no competing interests. 

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The animal experimental protocols were approved by the Institutional Animal Care and Use Committee of the Academy of Military Medical Science (AMMS) and all efforts were made to minimize animal suffering and reduce the number of animals used for the experiments.

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The animal experimental protocols were approved by the Institutional Animal Care and Use Committee of the Academy of Military Medical Science (AMMS). The manuscript does not contain clinical studies or patient data.

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Cite this article

Shang, C., Zhu, YL., Li, YQ. et al. Autophagy promotes oncolysis of an adenovirus expressing apoptin in human bladder cancer models. Invest New Drugs (2021). https://doi.org/10.1007/s10637-021-01073-x

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Keywords

  • Bladder cancer
  • Adenovirus
  • Autophagy
  • AMPK
  • Rapamycin