Physapubescin selectively induces apoptosis in VHL-null renal cell carcinoma cells through down-regulation of HIF-2α and inhibits tumor growth.

Lixia Chen,Guiyang Xia,Xiaolin Zi,Chunli Wu,Feng Qiu,Andria P Denmon

doi:10.1038/srep32582

Abstract

We have purified physapubescin, a predominant steroidal lactone, from medicinal plant Physalis pubescens L., commonly named as “hairy groundcherry” in English and “Deng-Long-Cao” in Chinese. Von Hippel-Lindau (VHL)-null 786-O, RCC4 and A498 Renal Cell Carcinoma (RCC) cell lines expressing high levels of Hypoxia Inducible Factor (HIF)-2α are more sensitive to physapubescin-mediated apoptosis and growth inhibitory effect than VHL wild-type Caki-2 and ACHN RCC cell lines. Restoration of VHL in RCC4 cells attenuated the growth inhibitory effect of physapubescin. Physapubescin decreases the expression of HIF-2α and increases the expression of CCAAT/enhancer-binding protein homologus protein (CHOP), which leads to up-regulation of death receptor 5 (DR5), activation of caspase-8 and -3, cleavage of poly (ADP-Ribose) polymerase (PARP) and apoptosis. Under hypoxia conditions, the apoptotic and growth inhibitory effects of physapubescin are further enhanced. Additionally, physapubescin synergizes with TNF-related apoptosis-inducing ligand (TRAIL) for markedly enhanced induction of apoptosis in VHL-null 786-O cells but not in VHL wild-type Caki-2 cells. Physapubescin significantly inhibited in vivo angiogenesis in the 786-O xenograft. Physapubescin as a novel agent for elimination of VHL-null RCC cells via apoptosis is warranted for further investigation.

Highlights

We have purified physapubescin, a predominant steroidal lactone, from medicinal plant Physalis pubescens L., commonly named as “hairy groundcherry” in English and “Deng-Long-Cao” in Chinese
Physapubescin was isolated from Physalis pubescens L. extracts and its chemical structure was identified by comparing its nuclear magnetic resonance (NMR) spectroscopic data with those of the published values
Since there is a close relationship among hypoxia, angiogenesis and vimentin and vimentin is a direct target of withaferin A, a well-studied withanolide[11], we examined the protein expression of vimentin in Von Hippel-Lindau (VHL) wild-type Caki-2 cells and VHL null 786-O cells after physapubescin and withaferin A treatments

Summary

Introduction

A predominant steroidal lactone, from medicinal plant Physalis pubescens L., commonly named as “hairy groundcherry” in English and “Deng-Long-Cao” in Chinese. Von Hippel-Lindau (VHL)-null 786-O, RCC4 and A498 Renal Cell Carcinoma (RCC) cell lines expressing high levels of Hypoxia Inducible Factor (HIF)-2α are more sensitive to physapubescin-mediated apoptosis and growth inhibitory effect than VHL wild-type Caki-2 and ACHN RCC cell lines. Since the first withanolide-type compound, withaferin A, was isolated from Withania somnifera in 19659, more than 750 withanolides with diversified functional groups have been identified from the Solanaceae family[10]. The structure-activity relationship analyses of these withanolides suggested that a Δ2−1-oxo-functionality in ring A and a 5β, 6β-epoxy in ring B were required for their cytotoxic activity[3,10] Among these withanolides, the anti-cancer mechanisms of withaferin A have been extensively studied and a key structural property, α, β-unsaturated ketone moiety in the A ring, identified. Inhibition of HIF-2αexpression and/or function would be an important approach for developing novel agents in treatment of ccRCC with loss of VHL

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Conclusion