title: Physapubescin selectively induces apoptosis in VHL-null renal cell carcinoma cells through down-regulation of HIF-2α and inhibits tumor growth.
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.
authors: Departments of Urology and Pharmacology, Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, CA 92868, USA.|Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design &Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China.
authors: Lixia
authors: L
authors: Chen
authors: Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Key Laboratory of Structure-Based Drug Design &Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China.
authors: Guiyang
authors: G
authors: Xia
authors: School of Chinese Materia Medica and Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P. R. China.
authors: Feng
authors: F
authors: Qiu
authors: Departments of Urology and Pharmacology, Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, CA 92868, USA.|Co-innovation Center of Henan Province for New Drug R &D and Preclinical Safety and School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, P. R. China.
authors: Chunli
authors: C
authors: Wu
authors: Departments of Urology and Pharmacology, Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, CA 92868, USA.
authors: Andria P
authors: AP
authors: Denmon
authors: Departments of Urology and Pharmacology, Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, CA 92868, USA.
authors: Xiaolin
authors: X
authors: Zi
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D032321:Physalis / Q000737:chemistry; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism; D054358:Withanolides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051792:Basic Helix-Loop-Helix Proteins; D053148:Caspase 3; D053181:Caspase 8; D011065:Poly(ADP-ribose) Polymerases; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D051742:Transcription Factor CHOP; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D054358:Withanolides; D000099162:Endothelial PAS Domain-Containing Protein 1; C497249:DDIT3 protein, human; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; C586239:physapubescin; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C497446:VHL protein, human