PodcastCancer

Science Signaling Podcast: 19 March 2013

Science Signaling  19 Mar 2013:
Vol. 6, Issue 267, pp. pc8
DOI: 10.1126/scisignal.2004109

Abstract

This Podcast features an interview with Ching-Shih Chen, senior author of a Research Article that appears in the 19 March 2013 issue of Science Signaling. Huang et al. report that the α and γ forms of tocopherol, which is a lipophilic molecule and dietary form of vitamin E, promoted dephosphorylation of the growth-promoting kinase Akt. Tocopherols bound to both Akt and the phosphatase PHLPP1 and recruited them to the plasma membrane, where PHLPP1 dephosphorylated Akt on Ser473, thus inactivating Akt. This reduced the proliferation of cultured prostate cancer cells and reduced the growth of prostate tumors xenografted into mice. The authors developed a synthetic derivative of γ-tocopherol that exhibited greater potency than natural tocopherols in this context, suggesting that the development of drugs structurally related to tocopherols might benefit the treatment of prostate and other cancers that are driven by Akt activity.

(Length: 14 min; file size: 7.9 MB; file format: mp3; location: http://podcasts.aaas.org/science_signaling/ScienceSignaling_130319.mp3)

Technical Details

Length: 14 min

File size: 7.9 MB

File Format: mp3

RSS Feed: http://stke.sciencemag.org/rss/podcast.xml

Listen to Podcast: http://podcasts.aaas.org/science_signaling/ScienceSignaling_130319.mp3

Educational Details

Learning Resource Type: Audio

Context: High school upper division 11-12, undergraduate lower division 13-14, undergraduate upper division 15-16, graduate, professional, general public and informal education

Intended Users: Teacher, learner

Intended Educational Use: Learn, teach

Discipline: Biochemistry, cell biology, human biology, pharmacology

Keywords: Science Signaling, Akt, dephosphorylation, PHLPP1, phosphatase, prostate cancer, PTEN, tocopherol, vitamin E

Transcript

Host – Annalisa VanHookWelcome to the Science Signaling Podcast for March 19th, 2013. I’m Annalisa VanHook, and today I’m speaking with Ching-Shih Chen about how vitamin E promotes inactivation of the kinase Akt.

There are several related compounds that are collectively referred to as vitamin E. These compounds fall into two classes—the tocopherols and the tocotrienols. Tocopherols are the compounds that are most commonly found in both foods and in dietary supplements. One of the many ways that vitamin E is hypothesized to exert its health benefits is by acting as an antioxidant. However, there’s also evidence that vitamin E has antitumor properties that may be independent of its antioxidant activity. For example, the α and γ forms of tocopherol can inhibit cell proliferation, but it’s not entirely clear how they do this. One of the mechanisms that’s been proposed to account for this observation is that tocopherols might inhibit activity at the kinase Akt, which plays an important role in the signaling events that control cell growth and metabolism. In a paper that appears in the current issue of Science Signaling, a group led by Ching-Shih Chen looked at the effect of tocopherols on Akt activity and report a mechanism by which tocopherols can promote dephosphorylation of Akt (1). Chen spoke to me from the College of Pharmacy at The Ohio State University.

Interviewer – Annalisa VanHookHello, Dr. Chen. Welcome to the Science Signaling Podcast.

Interviewee – Ching-Shih ChenWell, thank you for having me.

Interviewer – Annalisa VanHookBefore we talk about the results of this paper specifically, I want to talk a little bit about vitamin E in general. So, vitamin E has been promoted as having a lot of health benefits. What’s the evidence that vitamin E specifically has antitumor properties?

Interviewee – Ching-Shih ChenIn the literature, a wealth of preclinical data has demonstrated in vivo efficacy of high concentration[s] of vitamin E in suppressing the proliferation of different type[s] of cancer cells. And this antitumor activity is associated with the ability of vitamin E to induce apoptosis. And this antitumor property is also manifest in the chemopreventive effect of natural or synthetic forms of vitamin E in different animal models of tumorigenesis, including those of prostate, breast, colon, and pancreas.

Interviewer – Annalisa VanHookVitamin E has been proposed to act primarily as an antioxidant, but it’s also been implicated in regulating the activities of some enzymes and regulating gene transcription. How is vitamin E proposed to exert its antitumor effects—by being an antioxidant or changing gene transcription?

Interviewee – Ching-Shih ChenWell, several mechanisms have been proposed. And this has been the, you know, the focal point in the past 80 years. So, the health benefit of vitamin E—including its antitumor properties—are most often associated with its ability to reduce the production of reactive oxygen species and the free radicals, as you pointed out. And also, evidence suggest[s] the antitumor activity of vitamin E are also attributable to antioxidant-independent mechanism through its effect on enzyme regulation or gene expression. For example, α-tocopherol has been shown to suppress cyclooxygenase 2 activity; therefore, it blocks the biosynthesis of prostaglandins. Vitamin E also exhibit[s] effect[s] on transcription of gene[s] encoding key enzymes in the cholesterol biosynthesis pathway. In addition, it has been also shown to induce apoptosis in different type[s] of cancer cells through distinct mechanisms. For example, it has been reported to downregulate NF-κB signaling pathway or the inhibition of the expression of cell cycle regulated proteins, including cyclin D1 and cyclin E. However, how vitamin E target[s] this signaling pathway remain unclear.

Interviewer – Annalisa VanHookIn this paper, you looked molecularly at the effects of treating prostate cancer cells with both the α and the γ forms of tocopherol, and you focused specifically on the phosphorylation status of a kinase called Akt. How did tocopherols affect the phosphorylation and the activity of Akt?

Interviewee – Ching-Shih ChenWell, the tocopherols inhibit the phosphorylation of Akt at one of its two phosphorylation site[s]. And as you know, the Akt activity depending [sic] on the phosphorylation at the two site[s], which are Thr308 and Ser473. Therefore, the ability to inhibit this phosphorylation at Ser473 reduces its activity, causing the death of the cancer cells. So, specifically, we investigated the effect of α- and γ-tocopherol on the activation status of Akt in two prostate cancer cell lines. In these cells, the function of the tumor suppressor PTEN is deficient. So, PTEN is a negative regulator of PI3 kinase; therefore, this PTEN deficiency result[s] in the constituted activation of Akt, which is indicated by the high level of phosphorylation at the Thr308 and the Ser473 site[s]. So, our study indicate[s] that α- and γ-tocopherol selectively inhibit the phosphorylation of Akt at Ser473 without disturbing that of the Thr308. Therefore, it suppresses the activity of Akt.

Interviewer – Annalisa VanHookTocopherols don't mediate that dephosphorylation event themselves. How do tocopherols cause that particular serine residue—Ser473—to become dephosphorylated?

Interviewee – Ching-Shih ChenWell, it required the coordinated effort between Akt and another player, which is tumor suppressor called PHLPP1. PHLPP1 is the abbreviation for PH domain leucine-rich repeat protein phosphatase. So, PHLPP1 is a tumor suppressor that mediate[s] the selective dephosphorylation of Akt at the Ser473. So, our study indicate[s] that this selective dephosphorylation of Ser473 by tocopherol is mediated through a unique mechanism involving the membrane localization of Akt and PHLPP1. So, by facilitating the colocalization of this phosphatase with Akt, tocopherols are able to induce the selective dephosphorylation of Akt. And the membrane recruitment of Akt and PHLPP1 is mediated through the ability of tocopherol to recognize and bind the PH domains of these two proteins. As I mentioned earlier, the name of PHLPP1 contain[s] “PH domain,” so this is how it got recruited. And this recognition and binding is mediated through the, the head group of tocopherols, which the chemical structure is a so-called chroman. Moreover, through computer modeling and the mutational analysis, we were able to identify the chroman binding site within the Akt domain which provide[s] a structural basis to account for the higher antitumor potency of γ-tocopherol relative to α-tocopherol.

Interviewer – Annalisa VanHookAnd so, how do these results fit in with what’s already known about the regulation of Akt activity and Akt signaling in the progression of prostate cancer?

Interviewee – Ching-Shih ChenWell, this is a very important question. And in light of the important role of Akt signaling in regulating many aspect[s] of cell function, including proliferation, survival, and even metabolism in cancer cells, dysregulated Akt signaling is associated with oncogenesis and tumor progression in prostate and many other type[s] of cancer. The activation status of Akt is regulated, in part, through the negative regulation of two tumor suppressors—PTEN and PHLPP1. So, as I mentioned earlier, we focus[ed] on two PTEN-negative prostate cancer cell lines because this study address[ed] the issue of the role of PHLPP1 in regulating the Akt dephosphorylation in response to tocopherol. So, consequently, the relevance of our result to Akt signaling is two-fold. First, as I mentioned, we identified a mechanism that could activate PHLPP1-mediated Akt inactivation. Second, this novel finding provide[s] a mechanistic basis to use tocopherols—especially the γ form—as a scaffold to develop a new class of Akt inhibitors that target the PH domain–mediated membrane localization of Akt and PHLPP1. For example, in our study, based on the thermodynamics of the protein-ligand interaction in the interface between [the] cell membrane and the cytoplasm, we truncated the side chain of α- and γ-tocopherol to enhance the accessibility of the head group to the PH domain of Akt and PHLPP. So, the resulting derivatives we call the α- and the γ-VE5 show more than 20-fold higher antiproliferative potency relative to the α- and γ-tocopherols. The unique mechanisms of tocopherol to activate PHLPP1-mediated Akt phosphorylation provide a molecular basis to design a new class of Akt inhibitors that target both PHLPP1 and Akt to facilitate dephosphorylation of Akt. And the γ-VE5, as I indicated, which is a truncated form of γ-tocopherol, provide proof of concept for this drug discovery strategy.

Interviewer – Annalisa VanHookIn this study, you were using cultured prostate cancer cells. Did you look at the ability of tocopherols to inhibit tumor growth in an in vivo model—in tumors in whole animals?

Interviewee – Ching-Shih ChenWell, we did not test α- and γ-tocopherols for their in vivo efficacy to inhibit tumor growth because of their very low in vitro potency. Instead, we tested the ability of γ-VE5, as I mentioned, which is the more potent side chain–truncated derivative of γ-tocopherol, in two prostate xenograft tumor models in nude mice. And our data indicate that γ-VE5 could suppress the tumor growth in both models.

Interviewer – Annalisa VanHookAre these findings likely to apply to other types of cancer besides just prostate cancer? I know that’s what you were focusing on in this study, but what about other types of cancer and Akt signaling?

Interviewee – Ching-Shih ChenOh, yes, I think this pathway is also applicable to other type[s] of tumors besides prostate cancer. In light of the nearly universal role of Akt signaling in promoting tumorigenesis, it is likely that our finding has translational potential in prostate and other type[s] of cancer with dysregulated Akt signaling pathway due to PTEN mutation or growth factor receptor overexpression.

Interviewer – Annalisa VanHookDr. Chen, thank you for speaking with me.

Interviewee – Ching-Shih ChenWell, thank you. And it’s a great pleasure.

Host – Annalisa VanHookThat was Ching-Shih Chen, senior author of a paper that appears in the current issue of Science Signaling. That paper is by Huang and colleagues, and it’s titled “Vitamin E Facilitates the Inactivation of the Kinase Akt by the Phosphatase PHLPP1” (1).

music

And that wraps up this Science Signaling Podcast. If you have any questions or suggestions, you can send them to us at sciencesignalingeditors{at}aaas.org. This show is a production of Science Signaling and of AAAS—Advancing Science, Serving Society. I'm Annalisa VanHook, and on behalf of Science Signaling and its publisher, the American Association for the Advancement of Science, thanks for listening.

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