title: Piperlongumine promotes autophagy via inhibition of Akt/mTOR signalling and mediates cancer cell death.
abstract: BACKGROUND
  The Akt/mammalian target of rapamycin (mTOR) signalling pathway serves as a critical regulator of cellular growth, proliferation and survival. Akt aberrant activation has been implicated in carcinogenesis and anticancer therapy resistance. Piperlongumine (PL), a natural alkaloid present in the fruit of the Long pepper, is known to exhibit notable anticancer effects. Here we investigate the impact of PL on Akt/mTOR signalling.
  
  
  METHODS
  We examined Akt/mTOR signalling in cancer cells of various origins including prostate, kidney and breast after PL treatment. Furthermore, cell viability after concomitant treatment with PL and the autophagy inhibitor, Chloroquine (CQ) was assessed. We then examined the efficacy of in vivo combination treatment using a mouse xenograft tumour model.
  
  
  RESULTS
  We demonstrate for the first time that PL effectively inhibits phosphorylation of Akt target proteins in all tested cells. Furthermore, the downregulation of Akt downstream signalling resulted in decrease of mTORC1 activity and autophagy stimulation. Using the autophagy inhibitor, CQ, the level of PL-induced cellular death was significantly increased. Moreover, concomitant treatment with PL and CQ demonstrated notable antitumour effect in a xenograft mouse model.
  
  
  CONCLUSIONS
  Our data provide novel therapeutic opportunities to mediate cancer cellular death using PL. As such, PL may afford a novel paradigm for both prevention and treatment of malignancy.
authors.affiliation: Department of Surgical Oncology, Fox Chase Cancer Center of Temple University School of Medicine, Philadelphia, PA 19111, USA.
authors.forename: P
authors.initials: P
authors.lastname: Makhov
authors.affiliation: Department of Surgical Oncology, Fox Chase Cancer Center of Temple University School of Medicine, Philadelphia, PA 19111, USA.
authors.forename: K
authors.initials: K
authors.lastname: Golovine
authors.affiliation: Department of Surgical Oncology, Fox Chase Cancer Center of Temple University School of Medicine, Philadelphia, PA 19111, USA.
authors.forename: E
authors.initials: E
authors.lastname: Teper
authors.affiliation: Department of Surgical Oncology, Fox Chase Cancer Center of Temple University School of Medicine, Philadelphia, PA 19111, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kutikov
authors.affiliation: Department of Surgical Oncology, Fox Chase Cancer Center of Temple University School of Medicine, Philadelphia, PA 19111, USA.
authors.forename: R
authors.initials: R
authors.lastname: Mehrazin
authors.affiliation: Department of Surgical Oncology, Fox Chase Cancer Center of Temple University School of Medicine, Philadelphia, PA 19111, USA.
authors.forename: A
authors.initials: A
authors.lastname: Corcoran
authors.affiliation: Department of Surgical Oncology, Fox Chase Cancer Center of Temple University School of Medicine, Philadelphia, PA 19111, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tulin
authors.affiliation: Department of Surgical Oncology, Fox Chase Cancer Center of Temple University School of Medicine, Philadelphia, PA 19111, USA.
authors.forename: R G
authors.initials: RG
authors.lastname: Uzzo
authors.affiliation: Department of Surgical Oncology, Fox Chase Cancer Center of Temple University School of Medicine, Philadelphia, PA 19111, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Kolenko
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D004148:Dioxolanes / Q000494:pharmacology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy; D061986:MCF-7 Cells; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*; D017382:Reactive Oxygen Species; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D010881:Piperidones
chemical_list: D002738:Chloroquine; D004148:Dioxolanes; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C498077:piperlongumine; D010881:Piperidones