Selective CDK9 knockdown sensitizes TRAIL response by suppression of antiapoptotic factors and NF-kappaB pathway

Area of Science:

• Oncology
• Nanomedicine
• Molecular Biology

Background:

• Cyclin-dependent kinase 9 (CDK9) is aberrantly upregulated in cancer, presenting a therapeutic target.
• Dinaciclib (Dina), a CDK inhibitor, sensitizes cancer to TRAIL-expressing extracellular vesicles (EV-Ts) but has limited selectivity.
• There is a need for more selective and effective CDK9-targeted cancer therapies.

Purpose of the Study:

• To develop and evaluate a novel nanodrug, siEV-T, for cancer therapy by encapsulating CDK9-targeted siRNA (siCDK9) into EV-Ts.
• To assess the efficacy of siEV-T in suppressing CDK9 expression and overcoming TRAIL resistance in lung cancer.
• To elucidate the mechanism of action of siEV-T in inducing cancer cell apoptosis.

Main Methods:

• siCDK9 molecules were encapsulated into EV-Ts to create the siEV-T nanodrug.
• The efficacy of siEV-T in suppressing CDK9 expression was evaluated both in vitro and in vivo.
• Apoptosis induction and the underlying molecular mechanisms, including the nuclear factor-kappa B (NF-κB) pathway, were investigated.

Main Results:

• siEV-T efficiently suppressed CDK9 expression in lung cancer models.
• The nanodrug overcame TRAIL resistance and significantly augmented apoptosis in cancer cells.
• The mechanism involved the suppression of anti-apoptotic factors and the NF-κB pathway.

Conclusions:

• siEV-T represents a promising alternative to Dina for CDK9-targeted cancer therapy due to its enhanced selectivity and efficacy.
• The nanodrug demonstrates potential as a novel, highly effective, and safe therapeutic strategy for various cancers.
• siEV-T offers a new approach to cancer treatment by combining targeted gene silencing with drug delivery via extracellular vesicles.