Triptolide-induced apoptosis in non-small cell lung cancer via a novel miR204-5p/Caveolin-1/Akt-mediated pathway
Brian J. Philips, Ajay Kumar, Sarah Bürki, John P. Ryan, Kentaro Noda, Jonathan D’Cunha
Abstract
// Brian J. Philips 1 , Ajay Kumar 1 , Sarah Burki 1 , John P. Ryan 1 , Kentaro Noda 1 and Jonathan D’Cunha 2 1 Division of Lung Transplantation and Lung Failure, Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA, USA 2 Department of Cardiothoracic Surgery, Mayo Clinic, Phoenix, AZ, USA Correspondence to: Jonathan D’Cunha, email: [email protected] Keywords: triptolide; lung cancer; caveolin-1; miR204-5p; apoptosis Received: February 08, 2020     Accepted: April 14, 2020     Published: July 14, 2020 ABSTRACT Lung cancer is one of the most prevalent malignancies world-wide with non-small cell lung cancer (NSCLC) comprising nearly 80% of all cases. Unfortunately, many lung cancer patients are diagnosed at advanced stages of the disease with an associated poor prognosis. Recently, the Chinese herb root extract Triptolide/Minnelide (TL) has shown significant promise as a therapeutic agent for NSCLC treatment both in vitro and in vivo . The aim of this study was to investigate the underlying mechanism(s) of action regarding TL-induced cytotoxicity in NSCLC. We demonstrate that triptolide treatment of A549 and H460 NSCLC cells decreases Caveolin-1 (CAV-1) mRNA/protein expression, resulting in activation of the Akt/Bcl-2-mediated mitochondrial apoptosis pathway. CAV-1 down-regulation was triggered by Micro-RNA 204-5p (miR204-5p) up-regulation and could be significantly blocked by pre-treatment with both Sirt-1/Sirt-3 specific siRNA and SIRT-1/SIRT-3 enzyme inhibitors, EX-527 and nicotinamide. Overall, our results provide evidence for a novel mechanism by which TL exerts its cytotoxic effects on NSCLC via CAV-1 down-regulation. Furthermore, these findings demonstrate a pivotal role for TL induction of the Akt/Bax pathway in apoptosis of human lung cancer.