gamma-Tocopherol or combinations of vitamin E forms induce cell death in human prostate cancer cells by interrupting
Qing Jiang1, Jeffrey Wong, Henrik Fyrst
1Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA. qjiang@purdue.edu
Abstract:
gamma-Tocopherol (gammaT), the predominant form of vitamin E in diets, but not alpha-tocopherol, the major vitamin E form in tissues and supplements, inhibits proliferation of prostate cancer cells (LNCaP and PC-3) and lung cancer cells (A549). In contrast, at similar concentrations, gammaT has no effect on normal prostate epithelial cells. Combinations of some vitamin E forms, such as gammaT and delta-tocopherol, exhibit additive or synergistic inhibitory effects. In this study, gammaT or its combination with delta-tocopherol induced apoptosis in androgen-sensitive prostate LNCaP, but not in androgen-resistant PC-3 cells, by the induction of cytochrome c release, activation of caspase 9 and caspase 3, cleavage of poly-ADP-ribose polymerase (PARP), and involvement of caspase-independent pathways. Myriocin and fumonisin B1, specific inhibitors of key enzymes (serine palmitoyltransferase and dihydroceramide synthase, respectively) in de novo synthesis of sphingolipids, significantly protected cells from gammaT-induced DNA fragmentation, cytochrome c release, PARP cleavage, and the formation of active caspase 3. Compared with vehicle-treated controls, gammaT treatment led to pronounced dihydroceramide and dihydrosphingosine accumulation, which preceded morphological and biochemical manifestations of apoptosis. In contrast, ceramide and shpingosine levels did not increase until day 3, when substantial cell death took place. Our study demonstrates that gammaT and mixed vitamin E forms induce cell death by interrupting the de novo sphingolipid pathway in a prostate cancer cell line. Thus, certain vitamin E forms may be valuable as anticancer agents.
Insights
Gamma-tocopherol (gammaT), a form of vitamin E, inhibits prostate cancer cell growth by triggering apoptosis through the sphingolipid pathway. This vitamin E form shows potential as an anticancer agent.
Area of Science:
- Oncology
- Nutritional Science
- Biochemistry
Background:
- Gamma-tocopherol (gammaT), the primary dietary form of vitamin E, inhibits cancer cell proliferation.
- Unlike alpha-tocopherol, gammaT selectively targets cancer cells without affecting normal cells.
- Combinations of gammaT with other vitamin E forms, like delta-tocopherol, can enhance inhibitory effects.
Purpose of the Study:
- To investigate the mechanism by which gamma-tocopherol induces apoptosis in prostate cancer cells.
- To explore the role of the sphingolipid pathway in gammaT-mediated cell death.
- To evaluate the potential of gammaT and mixed vitamin E forms as anticancer agents.
Main Methods:
- Prostate cancer cell lines (LNCaP and PC-3) were treated with gamma-tocopherol and/or delta-tocopherol.
- Apoptosis was assessed by measuring cytochrome c release, caspase activation (caspase 9, caspase 3), and PARP cleavage.
- Sphingolipid metabolism was analyzed using specific enzyme inhibitors (myriocin, fumonisin B1) and by measuring lipid levels.
Main Results:
- Gamma-tocopherol induced apoptosis in androgen-sensitive LNCaP cells but not in androgen-resistant PC-3 cells.
- Apoptosis involved both caspase-dependent and caspase-independent pathways.
- GammaT treatment led to accumulation of dihydroceramide and dihydrosphingosine, indicating interruption of the de novo sphingolipid pathway.
- Inhibitors of sphingolipid synthesis protected cells from gammaT-induced apoptosis.
Conclusions:
- Gamma-tocopherol and mixed vitamin E forms induce prostate cancer cell death by disrupting the de novo sphingolipid pathway.
- The accumulation of specific sphingolipids precedes the induction of apoptosis.
- Certain vitamin E forms, particularly gamma-tocopherol, demonstrate potential as novel anticancer agents.
