Vitamin E succinate induces NAG-1 expression in a p38 kinase-dependent mechanism

Shim, Minsub; Eling, Thomas E.

doi:10.1158/1535-7163.mct-07-0470

Cited by 27 publications

(12 citation statements)

References 45 publications

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“…PLAB apoptotic-inducing activity has been observed and reported by other authors in several cellular contexts and following treatment with different anticancer agents [9], [18]-[21]. However, the specific downstream events by which PLAB mediates such effect remain to be determined.…”

Section: Discussionmentioning

confidence: 83%

4-oxo-N-(4-hydroxyphenyl)retinamide: Two Independent Ways to Kill Cancer Cells

et al. 2010

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BackgroundThe retinoid 4-oxo-N-(4-hydroxyphenyl)retinamide (4-oxo-4-HPR) is a polar metabolite of fenretinide (4-HPR) very effective in killing cancer cells of different histotypes, able to inhibit 4-HPR-resistant cell growth and to act synergistically in combination with the parent drug. Unlike 4-HPR and other retinoids, 4-oxo-4-HPR inhibits tubulin polymerization, leading to multipolar spindle formation and mitotic arrest. Here we investigated whether 4-oxo-4-HPR, like 4-HPR, triggered cell death also via reactive oxygen species (ROS) generation and whether its antimicrotubule activity was related to a ROS-dependent mechanism in ovarian (A2780), breast (T47D), cervical (HeLa) and neuroblastoma (SK-N-BE) cancer cell lines.Methodology/Principal FindingsWe provided evidence that 4-oxo-4-HPR, besides acting as an antimicrotubule agent, induced apoptosis through a signaling cascade starting from ROS generation and involving endoplasmic reticulum (ER) stress response, Jun N-terminal Kinase (JNK) activation, and upregulation of the proapoptotic PLAcental Bone morphogenetic protein (PLAB). Through time-course analysis and inhibition of the ROS-related signaling pathway (upstream by vitamin C and downstream by PLAB silencing), we demonstrated that the antimitotic activity of 4-oxo-4-HPR was independent from the oxidative stress induced by the retinoid. In fact, ROS generation occurred earlier than mitotic arrest (within 30 minutes and 2 hours, respectively) and abrogation of the ROS-related signaling pathway did not prevent the 4-oxo-4-HPR-induced mitotic arrest.Conclusions/SignificanceThese data indicate that 4-oxo-4-HPR anticancer activity is due to at least two independent mechanisms and provide an explanation of the ability of 4-oxo-4-HPR to be more potent than the parent drug and to be effective also in 4-HPR-resistant cell lines. In addition, the double mechanism of action could allow 4-oxo-4-HPR to efficiently target tumour and to eventually counteract the development of drug resistance.

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Section: Discussionmentioning

confidence: 83%

4-oxo-N-(4-hydroxyphenyl)retinamide: Two Independent Ways to Kill Cancer Cells

et al. 2010

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“…As a control, PMA was used to activate PKC signaling transduction pathway. PMA was also known to be capable of increasing GDF15 expression through the activation of PKC in prostate cancer cells (Shim and Eling, 2005, 2008). Treating PC3 cells with 300 nM PMA increased GDF15 protein levels within 8 h (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…These inhibitors were chosen based on previously observed findings that activation of protein kinase C (PKC) or p38 mitogen-activated protein kinase (p38MAPK) through the addition of phorbol 12-myristate 13-acetate (PMA) or vitamin E respectively up-regulates GDF15 expression (Shim and Eling, 2005, 2008). …”

Section: Methodsmentioning

confidence: 99%

Morphological Effects on Expression of Growth Differentiation Factor 15 (GDF15), a Marker of Metastasis

Yong

Zeng

Vindivich

et al. 2013

Journal Cellular Physiology

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Cancer cells typically demonstrate altered morphology during the various stages of disease progression as well as metastasis. While much is known about how altered cell morphology in cancer is a result of genetic regulation, less is known about how changes in cell morphology affect cell function by influencing gene expression. In this study, we altered cell morphology in different types of cancer cells by disrupting the actin cytoskeleton or by modulating attachment and observed a rapid up-regulation of growth differentiation factor 15 (GDF15), a member of the transforming growth factor-beta (TGF-β) super-family. Strikingly, this up-regulation was sustained as long as the cell morphology remained altered but was reversed upon allowing cell morphology to return to its typical configuration. The potential significance of these findings was examined in vivo using a mouse model: a small number of cancer cells grown in diffusion chambers that altered morphology increased mouse serum GDF15. Taken together, we propose that during the process of metastasis, cancer cells experience changes in cell morphology, resulting in the increased production and secretion of GDF15 into the surrounding environment. This indicates a possible relationship between serum GDF15 levels and circulating tumor cells may exist. Further investigation into the exact nature of this relationship is warranted.

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“…Pro-and antitumor activities have been described for GDF15 and a role in resistance to chemotherapy (11,(19)(20)(21)(22)(23)(24)(25). Overexpression of this factor reduces the tumorigenic potential of some cancer cells, but enhances the protumorigenic activity of other cancer cells (21,(26)(27)(28)(29)(30).…”

Section: Introductionmentioning

confidence: 99%

Local and Systemic Protumorigenic Effects of Cancer-Associated Fibroblast-Derived GDF15

et al. 2014

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The tumor stroma is vital to tumor development, progression, and metastasis. Cancer-associated fibroblasts (CAF) are among the abundant cell types in the tumor stroma, but the range of their contributions to cancer pathogenicity has yet to be fully understood. Here, we report a critical role for upregulation of the TGFb/BMP family member GDF15 (MIC-1) in tumor stroma. GDF15 was found upregulated in situ and in primary cultures of CAF from prostate cancer. Ectopic expression of GDF15 in fibroblasts produced prominent paracrine effects on prostate cancer cell migration, invasion, and tumor growth. Notably, GDF15-expressing fibroblasts exerted systemic in vivo effects on the outgrowth of distant and otherwise indolent prostate cancer cells. Our findings identify tumor stromal cells as a novel source of GDF15 in human prostate cancer and illustrate a systemic mechanism of cancer progression driven by the tumor microenvironment. Further, they provide a functional basis to understand GDF15 as a biomarker of poor prognosis and a candidate therapeutic target in prostate cancer. Cancer Res; 74(13); 3408-17. Ó2014 AACR.

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Vitamin E succinate induces NAG-1 expression in a p38 kinase-dependent mechanism

Cited by 27 publications

References 45 publications

4-oxo-N-(4-hydroxyphenyl)retinamide: Two Independent Ways to Kill Cancer Cells

4-oxo-N-(4-hydroxyphenyl)retinamide: Two Independent Ways to Kill Cancer Cells

Morphological Effects on Expression of Growth Differentiation Factor 15 (GDF15), a Marker of Metastasis

Local and Systemic Protumorigenic Effects of Cancer-Associated Fibroblast-Derived GDF15

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