Ad-VT oncolytic adenovirus suppresses bladder cancer via cAMP-dependent AMPK-Raptor activation and G2/M arrest

Area of Science:

• Oncolytic virotherapy
• Molecular oncology
• Cancer cell biology

Background:

• Bladder cancer is a significant cause of cancer mortality with limited treatment options.
• Oncolytic viruses offer a promising approach for targeted cancer therapy.
• Understanding the molecular mechanisms of oncolytic viruses is crucial for optimizing their efficacy.

Purpose of the Study:

• To investigate the antitumor efficacy and mechanism of Ad-VT, a dual-specific oncolytic adenovirus, in bladder cancer.
• To determine the selectivity of Ad-VT against bladder cancer cells versus normal urothelial cells.
• To elucidate the signaling pathways involved in Ad-VT-mediated cytotoxicity.

Main Methods:

• In vitro cytotoxicity assays using bladder cancer cell lines and normal urothelial cells.
• Cell cycle analysis and Western blotting to assess molecular changes.
• In vivo studies using bladder cancer xenografts in mice.
• Pharmacological inhibition and siRNA knockdown of key signaling pathway components.

Main Results:

• Ad-VT demonstrated selective killing of bladder cancer cells, inducing dose-dependent cytotoxicity.
• Ad-VT caused G2/M phase arrest by modulating cell cycle regulatory proteins.
• The virus elevated cAMP levels, activating the AMPK-Raptor-mTOR pathway, which was essential for its effects.
• In vivo, Ad-VT suppressed tumor growth, increased apoptosis, and enhanced survival, with AMPK pathway activation being critical.

Conclusions:

• Ad-VT exhibits potent and tumor-selective antitumor activity against bladder cancer.
• The mechanism involves induction of cAMP-dependent AMPK-Raptor-mTOR signaling and G2/M cell cycle arrest.
• Ad-VT represents a promising therapeutic candidate for bladder cancer treatment.