title: Gamma-tocotrienol induces apoptosis and autophagy in prostate cancer cells by increasing intracellular dihydrosphingosine and dihydroceramide.
abstract: Although cell-based studies have shown that γ-tocotrienol (γTE) exhibits stronger anticancer activities than other forms of vitamin E including γ-tocopherol (γT), the molecular bases underlying γTE-exerted effects remains to be elucidated. Here we showed that γTE treatment promoted apoptosis, necrosis and autophagy in human prostate PC-3 and LNCaP cancer cells. In search of potential mechanisms of γTE-provoked effects, we found that γTE treatment led to marked increase of intracellular dihydroceramide and dihydrosphingosine, the sphingolipid intermediates in de novo sphingolipid synthesis pathway but had no effects on ceramide or sphingosine. The elevation of these sphingolipids by γTE preceded or coincided with biochemical and morphological signs of cell death and was much more pronounced than that induced by γT, which accompanied with much higher cellular uptake of γTE than γT. The importance of sphingolipid accumulation in γTE-caused fatality was underscored by the observation that dihydrosphingosine and dihydroceramide potently reduced the viability of both prostate cell lines and LNCaP cells, respectively. In addition, myriosin, a specific inhibitor of de novo sphingolipid synthesis, counteracted γTE-induced cell death. In agreement with these cell-based studies, γTE inhibited LNCaP xenograft growth by 53% (p < 0.05), compared to 33% (p = 0.07) by γT, in nude mice. These findings provide a molecular basis of γTE-stimulated cancer cell death and support the notion that elevation of intracellular dihydroceramide and dihydrosphingosine is likely a novel anticancer mechanism.
authors.affiliation: Department of Foods and Nutrition, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN 47907, USA. qjiang@purdue.edu
authors.forename: Qing
authors.initials: Q
authors.lastname: Jiang
authors.forename: Xiayu
authors.initials: X
authors.lastname: Rao
authors.forename: Choon Young
authors.initials: CY
authors.lastname: Kim
authors.forename: Helene
authors.initials: H
authors.lastname: Freiser
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Zhang
authors.forename: Ziying
authors.initials: Z
authors.lastname: Jiang
authors.forename: Guilan
authors.initials: G
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001343:Autophagy; D045744:Cell Line, Tumor; D002470:Cell Survival; D002518:Ceramides / Q000378:metabolism*; D002839:Chromans / Q000494:pharmacology*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002518:Ceramides; D002839:Chromans; C109343:dihydroceramide; D014810:Vitamin E; C013649:plastochromanol 8; D051057:Proto-Oncogene Proteins c-akt; D013110:Sphingosine; C005682:safingol; D008798:Mevalonic Acid