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Abstract
Our previous studies indicated that combination of Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and PPARγ ligand Troglitazone (TZD), can induce significant apoptosis in various TRAIL-resistant prostate and hepatocellular carcinoma (HCC) cells. These also suggested serine/threonine kinase AMP-activated protein kinase (AMPK) to be a mediator of TRAIL-TZD-induced apoptosis. To further validate AMPK’s role in TRAIL sensitization, we determined the apoptotic potential of TRAIL in combination with the natural compound Berberine (BBR), the latter being a potent activator of AMPK. These demonstrated a significant reduction of cell viability and induction of apoptosis (increased cleavage of caspase 3, 8, 9) when treated with TRAIL-BBR combination. This apoptosis is attenuated in cells overexpressing AMPKα-dominant negative (DN) or following AMPKα knockdown, confirming involvement of AMPK. To identify potential downstream mediators involved, an apoptosis RT2 PCR array analysis was performed. These showed induction of several genes including TNFRSF10B (expresses DR5) and Harakiri following BBR treatment, which were further validated by qPCR analysis. Furthermore, knocking down DR5 expression significantly attenuated TRAIL-BBR-induced apoptosis, suggesting DR5 to be a mediator of this apoptosis. Our studies indicate that combination of TRAIL and AMPK activator BBR might be an effective means of ameliorating TRAIL-resistance involving DR5 in advanced cancer.
Highlights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) belongs to the tumor necrosis factor (TNF) ligand superfamily and has been studied extensively for its potential use as a cancer chemotherapeutic agent due to its low toxicity towards normal tissue[1,2]
We have demonstrated that combination of TRAIL along with TZD can induce potent apoptosis in various resistant cancer cells, an effect that involved AMPK13
To elucidate the mechanism involved, in more recent studies we have demonstrated that AMPK pathway is involved in mediating TRAIL-TZD combination-induced apoptosis[13]
Summary
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) belongs to the tumor necrosis factor (TNF) ligand superfamily and has been studied extensively for its potential use as a cancer chemotherapeutic agent due to its low toxicity towards normal tissue[1,2]. Extensive research over the past decade have revealed some novel combinatorial approaches that can increase cancer cell sensitivity towards TRAIL-induced cytotoxicity These TRAIL-sensitizing agents include kinase inhibitors[6,7], Peroxisome Proliferator-activated Receptor γ (PPARγ) agonists[8,9], histone deacetylase inhibitors[10] and more[11,12]. Further insight towards the mechanism involved demonstrated that TRAIL and TZD combination-induced apoptosis was mediated via Adenosine monophosphate-activated protein kinase (AMPK) pathway[13]. Knockdown studies designed with DR4 or DR5 specific siRNA indicated that TRAIL-BBR-induced apoptosis is mediated predominantly by DR5 These promising results demonstrate the potential to use BBR in ameliorating TRAIL-resistance in advanced forms of cancer and sheds light towards its clinical importance, since no negative side effects of BBR in human is known so far
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