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Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various tumor cells without affecting most normal cells. Despite being in clinical testing, novel strategies to induce TRAIL-mediated apoptosis are in need to overcome cancer cell unresponsiveness and resistance. Plasma-activated medium (PAM) markedly stimulates reactive oxygen/nitrogen species (ROS/RNS)-dependent apoptosis in cancer cells. We investigate the capability of PAM and TRAIL (PAM/TRAIL) combination therapy to overcome TRAIL resistance and improve the anticancer efficacy of TRAIL. The combinatorial treatment of PAM and TRAIL shows synergistic effects on growth inhibition in TRAIL-resistant cancer cells via augmented apoptosis by two attributes. DR5 (TRAIL-R2) transcription by CHOP is upregulated in a PAM-generated ROS/RNS-dependent manner, and PAM itself upregulates PTEN expression mediated by suppression of miR-425 which is involved in Akt inactivation, leading to increased apoptosis induction. Treatment of cancer cell lines with the antioxidant N-acetylcysteine reduces the extent of membrane dysfunction and the expression of both CHOP-DR5 and miR-425-PTEN axes, attenuating PAM/TRAIL-induced cancer cell apoptosis. These data suggest that PAM/TRAIL treatment is a novel approach to sensitizing cancer cells to TRAIL-induced apoptosis and overcoming TRAIL resistance. PAM is a promising candidate for further investigations as a chemotherapeutic sensitizer in the treatment of cancer.
Highlights
Apoptosis can be triggered through both intrinsically and extrinsically initiated pathways
PinAgMPASeMnsiotrizPeAs CMa/nTcRerACIeLlltsrteoatTmReAnItL,lIenvdeulcseodfAPpToEptNospisrovitaeiMn,oadnuluatpiosntreoaf mmiRph-4o2s5p-hPaTtEaNse-AofktAAkxtis signal pathway, were markedly increased, and phosphorylated Akt levels were decreased in HeLa cells (Figure 6a). These results demonstrate that Plasma-activated medium (PAM)-induced PTEN upregulation, leading to Akt inactivation, contributes to Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis by PAM
We found that the antioxidant NAC significantly ameliorated PAM-induced TRAIL-mediated apoptosis with concomitant recovery of Ca2+ homeostasis and the abolishment of DR5 upregulation, confirming that reactive oxygen species (ROS)/RNS plays a crucial role in PAM-induced TRAIL sensitization
Summary
Apoptosis can be triggered through both intrinsically and extrinsically initiated pathways. Most current chemotherapeutic strategies target the dysregulation of apoptotic pathways in cancer cells. Intrinsic pathways are initiated at the mitochondria level in a p53-dependent manner [1]. Conventional radio- and chemotherapies aim mainly at the p53-dependent intrinsic apoptotic pathway. More than half of human cancers carry the loss of p53 function, and are either initially resistant or eventually acquire resistance to these treatments. Many cancers continue to survive and thrive because of the lack of p53 function in intrinsic cellular apoptotic mechanisms. P53 appears to be dispensable for extrinsic apoptotic pathways in most cancers. Extrinsic pathways are triggered by the binding of death ligands to death receptors (DRs) found in the cellular membrane
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