Molecular mechanism of α-tocopheryl-phosphate transport across the cell membrane

Negis, Yesim; Meydani, Mohsen; Zingg, Jean‐Marc; Azzi, Angelo

doi:10.1016/j.bbrc.2007.05.094

Cited by 34 publications

(30 citation statements)

References 28 publications

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“…For the transport of aT across the plasma membrane, the ATP binding cassette transporter A1 [33][34][35] and the multidrug resistance protein P-glycoprotein [36,37] have been identified. For the import of aT, the LDL receptor [38] and the scavenger receptor SR-BI has been described [39], whereas glybenclamide sensitive organic anion transporters have been suggested as aTP transmembrane carriers [29]. Uptake and hydrolysis of aTP in isolated hepatocytes was increased when extracellular [Ca 21 ] was depleted, suggesting that the cellular [Ca 21 ] content modulates the transport efficiency and metabolism of aTP [40].…”

Section: Lipid Transport Proteins With Possible Role In At and Atp Fumentioning

confidence: 97%

“…aT can also become phosphorylated in vivo, as demonstrated by feeding rats with radioactive [ 14 C]-aT as precursor and isolating the labeled aTP from the liver [20]. Other studies suggest that aTP can be de-phosphorylated at a low rate in cell lines (THP-1 monocytes and human brain microvascular endotheliocytes) [21,29,30], in microsomal and mitochondrial suspensions [31], as well as in vivo in mouse keratinocytes and in rabbits [24,28]. …”

Section: Interconversion Of At and Atp By Kinases And Phosphatasesmentioning

confidence: 98%

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α‐Tocopheryl phosphate – An active lipid mediator?

Zingg

Meydani

Azzi

2010

Molecular Nutrition Food Res

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The vitamin E (alpha-tocopherol, alphaT) derivative, alpha-tocopheryl phosphate (alphaTP), is detectable in small amounts in plasma, tissues, and cultured cells. Studies done in vitro and in vivo suggest that alphaT can become phosphorylated and alphaTP dephosphorylated, suggesting the existence of enzyme(s) with alphaT kinase or alphaTP phosphatase activity, respectively. As a supplement in animal studies, alphaTP can reach plasma concentrations similar to alphaT and only a part is dephosphorylated; thus, alphaTP may act both as pro-vitamin E, but also as phosphorylated form of vitamin E with possibly novel regulatory activities. Many effects of alphaTP have been described: in the test tube alphaTP modulates the activity of several enzymes; in cell culture alphaTP affects proliferation, apoptosis, signal transduction, and gene expression; in animal studies alphaTP prevents atherosclerosis, ischemia/reperfusion injury, and induces hippocampal long-term potentiation. At the molecular level, alphaTP may act as a cofactor for enzymes, as an active lipid mediator similar to other phosphorylated lipids, or indirectly by altering membrane characteristics such as lipid rafts, fluidity, and curvature. In this review, the molecular and cellular activities of alphaTP are examined and the possible functions of alphaTP as a natural compound, cofactor and active lipid mediator involved in signal transduction and gene expression discussed.

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Section: Lipid Transport Proteins With Possible Role In At and Atp Fumentioning

confidence: 97%

Section: Interconversion Of At and Atp By Kinases And Phosphatasesmentioning

confidence: 98%

α‐Tocopheryl phosphate – An active lipid mediator?

Zingg

Meydani

Azzi

2010

Molecular Nutrition Food Res

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“…The differential cell uptake of vitamin E forms could involve specific transporters such as the organic anion transport system (Negis et al 2007), but also direct membrane transfer and intramembrane diffusion and interaction mechanisms that appear to favor the uptake and bioactivity of HM T3 forms (Palozza et al 2006). The rapid and massive uptake of d-T3 and in general of HM forms in cancer cells may influence the lipid structure and key functional domains of the plasmalemma (Atkinson et al 2010).…”

Section: Metabolite Formation and Activitymentioning

confidence: 99%

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

et al. 2011

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The selective constraint of liver uptake and the sustained metabolism of tocotrienols (T3) demonstrate the need for a prompt detoxification of this class of lipophilic vitamers, and thus the potential for cytotoxic effects in hepatic and extra-hepatic tissues. Hypomethylated (c and d) forms of T3 show the highest in vitro and in vivo metabolism and are also the most potent natural xenobiotics of the entire vitamin E family of compounds. These stimulate a stress response with the induction of detoxification and antioxidant genes. Depending on the intensity of this response, these genes may confer cell protection or alternatively they stimulate a senescence-like phenotype with cell cycle inhibition or even mitochondrial toxicity and apoptosis. In cancer cells, the uptake rate and thus the cell content of these vitamers is again higher for the hypomethylated forms, and it is the critical factor that drives the dichotomy between protection and toxicity responses to different T3 forms and doses. These aspects suggest the potential for marked biological activity of hypomethylated ''highly metabolized'' T3 that may result in cytoprotection and cancer prevention or even chemotherapeutic effects. Cytotoxicity and metabolism of hypomethylated T3 have been extensively investigated in vitro using different cell model systems that will be discussed in this review paper as regard molecular mechanisms and possible relevance in cancer therapy.Keywords Tocotrienols Á Vitamin E Á Breast cancer Á Antioxidants Á Apoptosis Á Cell signaling Á Inflammation Á Metabolism Á Gene expression Á Cell redox T3 structure-function and specificity of actionIn the vitamin E family of molecules, tocotrienols (T3) are often considered of minor importance since these are less abundant than a and c tocopherol (TOH) in the circulation and in solid tissues. This has contributed to hinder our knowledge on the biological functions of this group of vitamers that is now regaining great interest, thanks to a number of recent studies that suggested health-promoting functions related with the cholesterol-lowering, cytoprotective, and anticarcinogenic effects of T3 [reviewed in (Aggarwal et al. (2010)].Structure-function studies demonstrate that many of these functions are more potent when the unsaturated (isoprenyl) side chain of T3 is combined with a hypomethylated (HM) chroman ring. The unsaturated chain characteristic of all the T3 forms confers well-defined physical and chemical characteristics that appear to include vitamer-specific interactions with other lipids and cell proteins (Atkinson

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“…Thus, it seems that the antioxidant activities of TocP are not mainly involved in the repressive effects on tumor invasion, and the anti-invasive effect of TocP seems to be due to the effect of the parent compound Toc. It has been also shown that TocP is highly resistant to hydrolysis by both chemical and enzymatic actions, which indicates that its effect is not related to the hydrolytic conversion to free tocopherol (4,7,9,10,43). Furthermore, it was shown that TocP has a more marked potency than the non-esterified molecule in several studies (4,(8)(9)(10).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies suggested that the TocP transport into cells may occur via organic anion transporters (OAT) (43), and TocP may act as a signaling molecule (4,5). It has been reported that supplementation with TocP affects the several signaling molecules such as anti-apoptotic p42/44 ERK kinase, p38 MAPKß, pro-apoptotic proteins p38 MAPK·, JNK, DNA binding of the redox-sensitive transcriptional factor NFκB, anti-death protein Bcl-2 and survival signaling protein Akt (5).…”

Section: Discussionmentioning

confidence: 99%

α-tocopheryl phosphate suppresses tumor invasion concurrently with dynamic morphological changes and delocalization of cortactin from invadopodia

Saitoh

Yumoto²,

Miwa³

2009

Int J Oncol

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Abstract. ·-tocopheryl phosphate (TocP) has been elucidated for diverse effectiveness through unequivocal mechanisms independent of its conversion to ·-tocopherol (Toc). The present study showed that TocP, in a dose-dependent manner, repressed invasion of human fibrosarcoma HT-1080 cells through the basement membrane, more markedly than Toc and several other Toc derivatives, although no cytotoxic effect was shown in either HT-1080 cells or human skin dermal fibroblastic cells DUMS-16. TocP diminished intracellular reactive oxygen species such as peroxides, lipid hydroperoxides and superoxide anion radicals in HT-1080 cells, but the effects were nearly equal or less than those of Toc. TocP suppressed either the cell motility or adhesion to extracellular matrix (ECM), and induced diagnostic morphological changes such as appearance of numerous spikeshaped processes and vesicles. Localization of cortactin in the membrane of invadopodia, which dispatches signal transduction for tumor invasion, was lost by TocP as shown by immunostaining. Similar result was obtained also by Western blots showing that cortactin in the membrane fraction was markedly diminished by TocP in contrast to unchanged cortactin amounts in other subcellular fractions including nuclei, cytoplasms and cytoskeletons. In contrast, TocP scarcely affected the invasiveness-related gelatinases MMP-2/9 and cell membrane fluidity. Thus, TocP markedly exerted anti-invasive activities through decrease in cell motility, repression of adhesion to the ECM, cell morphological changes and, especially, alteration of cortactin distribution. Moreover, TocP also preferentially inhibited tumor invasion without cytotoxicity to normal cells derived from the corresponding tissue type. Consequently, TocP is suggested as a potent tumor-invasion suppressor.

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Molecular mechanism of α-tocopheryl-phosphate transport across the cell membrane

Cited by 34 publications

References 28 publications

α‐Tocopheryl phosphate – An active lipid mediator?

α‐Tocopheryl phosphate – An active lipid mediator?

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

α-tocopheryl phosphate suppresses tumor invasion concurrently with dynamic morphological changes and delocalization of cortactin from invadopodia

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