Oncotarget: Triptolide-induced apoptosis in non-small cell lung cancer


Oncotarget recently published "Triptolide-induced apoptosis in non-small cell lung cancer via a novel miR204-5p/Caveolin-1/Akt-mediated pathway" which reported that Lung cancer is one of the most prevalent malignancies worldwide with non-small cell lung cancer comprising nearly 80% of all cases.

Unfortunately, many lung cancer patients are diagnosed at advanced stages of the disease with an associated poor prognosis.

The authors demonstrate that triptolide treatment of A549 and H460 NSCLC cells decreases Caveolin-1 mRNA/protein expression, resulting in activation of the Akt/Bcl-2-mediated mitochondrial apoptosis pathway.

Overall, their results provide evidence for a novel mechanism by which TL exerts its cytotoxic effects on NSCLC via CAV-1 down-regulation.

Furthermore, the Oncotarget author's findings demonstrate a pivotal role for TL induction of the Akt/Bax pathway in apoptosis of human lung cancer.

The Oncotarget author's findings demonstrate a pivotal role for TL induction of the Akt/Bax pathway in apoptosis of human lung cancer

Dr. Jonathan D'Cunha from The Mayo Clinic said, "Triptolide (TL), a diterpenoid triepoxide isolated from the Chinese plant Tripterygium wilfordii Hook F [1], is known to possess anti-inflammatory, immunosuppressive, and anti-tumor activities."

Moreover, their group has demonstrated that p53 deficiency exacerbates the cytotoxic effects of TL in NSCLC and that TL impairs mitochondria function in a p53-dependent manner by SIRT-3 regulation.

However, despite its known anti-proliferative/pro-apoptotic effects on NSCLC in vitro, the potential impact of TL on CAV-1 expression in lung cancer cells is unknown.

Because the precise mechanism of the anti-lung cancer activities of TL is incompletely defined, we sought to determine if TL treatment of lung cancer cells affects both CAV-1 expression and overall cell viability.

The authors also demonstrate that TL significantly up-regulates miR-204-5p expression in both cell lines, resulting in decreased CAV-1 expression.

Figure 7: Signal transduction cascade mediating TL-induced apoptosis in NSCLC.

Figure 7: Signal transduction cascade mediating TL-induced apoptosis in NSCLC. TL decreases protein expression of both SIRT-1 and SIRT-3 through independent pathways resulting in mitochondrial dysfunction in NSCLC.

Their in vitro findings suggest a novel mechanistic pathway by which TL triggers NSCLC cell death via CAV-1 down-regulation.

The D'Cunha Research Team concluded in their Oncotarget Research Paper that Inhibition of miR-204-5p via siRNA is able to effectively block TL-induced CAV-1 protein down-regulation in both A549 and NCI-H460 NSCLC cell lines.

These findings strongly suggest a link between miR-204-5p and SIRT-1:-3/CAV-1 expression in mediating the apoptotic effects of TL in NSCLC and indicate a novel mechanism by which TL, via miR204-5p up-regulation and associated CAV-1 down-regulation, triggers the activation of mitochondria-mediated apoptosis in NSCLC.

Mechanistically, TL decreases phosphorylation of Akt, causing Bcl-2 down-regulation and Bax up-regulation, culminating in caspase-3 activation and cleavage of PARP.

In this scenario, nuclear full-length SIRT-3, following TL treatment of NSCLC, likely mediates Cav-1 mRNA down-regulation either directly or indirectly.

Overall, this study proposes new insight into the mechanistic basis of TL-induced mitochondria-mediated apoptosis involving miR204-5p/CAV-1 and provides a rationale for future clinical investigation of the therapeutic efficacy of TL in NSCLC patients.

DOI - https://doi.org/10.18632/oncotarget.27672

Full text - https://www.oncotarget.com/article/27672/text/

Correspondence to - Jonathan D'Cunha - [email protected]

Keywords - triptolide, lung cancer, caveolin-1, miR204-5p, apoptosis

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