title: Cucurbitacin IIa: a novel class of anti-cancer drug inducing non-reversible actin aggregation and inhibiting survivin independent of JAK2/STAT3 phosphorylation.
abstract: BACKGROUND
  Cucurbitacin (Cuc) and triterpene-derived natural products exhibit anti-cancer potential in addition to their conspicuous anti-bacterial and anti-inflammatory activity. Recently, inhibition of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling was shown to underlie the effects of Cuc family on inducing cell death in cancer.
  
  
  METHODS
  We purified Cuc IIa, the active component from the medicinal plant Hemsleya amalils Diels, which shows different structural modifications from other Cuc derivatives. We investigated the mechanisms of its inhibitory effects on cancer cells in vitro and tumour growth in vivo.
  
  
  RESULTS
  Cuc IIa induced the irreversible clustering of filamentous actin and arrested cell cycle by the increases in G2/M populations. Cuc IIa resulted in the reduced phospho-Histone H3 and markedly increased cleavage of poly-(ADP-ribose) polymerase or PARP, immediate upstream of DNA breakdown as the result of caspase activation, consistent with mitotic blockage-induced cell death. However, unlike other Cuc members, Cuc IIa did not suppress JAK2/STAT3 phosphorylation or alter phosphorylation of mitogen-activated protein kinases. Instead, the expression of the cell cycle-regulated Inhibitor of Apoptosis Protein (IAP) survivin was reduced. Introducing oncoprotein δ-catenin, which increased survivin expression and suppressed small GTPase RhoA, reduced efficacy of Cuc IIa to induce cell death. Supporting the effects of Cuc IIa on actin cytoskeletal signaling, RhoA phosphorylation was reduced suggesting its increased activity.
  
  
  CONCLUSIONS
  Cuc IIa is a novel class of anti-cancer drug in suppression of cancer cell expansion by disrupting the actin cytoskeleton and directing the cell to undergo PARP-mediated apoptosis through the inhibition of survivin downstream of JAK2/STAT3.
authors.affiliation: Department of Anatomy and Cell Biology, East Carolina University, Greenville, NC 27834, USA.
authors.forename: C
authors.initials: C
authors.lastname: Boykin
authors.forename: G
authors.initials: G
authors.lastname: Zhang
authors.forename: Y-H
authors.initials: YH
authors.lastname: Chen
authors.forename: R-W
authors.initials: RW
authors.lastname: Zhang
authors.forename: X-E
authors.initials: XE
authors.lastname: Fan
authors.forename: W-M
authors.initials: WM
authors.lastname: Yang
authors.forename: Q
authors.initials: Q
authors.lastname: Lu
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D054728:Cucurbitacins / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D053614:Janus Kinase 2 / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010766:Phosphorylation; D012097:Repressor Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D000077022:Survivin
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D000077022:Survivin; C557526:cucurbitacin IIa; D054728:Cucurbitacins; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2