Activation of Dual Apoptotic Pathways in Human Melanocytes and Protection by Survivin

Liu, Tong; Biddle, Diana; Hanks, Adrianne N.; Brouha, Brook; Yan, Hui; Lee, Ray M.; Leachman, Sancy A.; Grossman, Douglas

doi:10.1038/sj.jid.5700381

Cited by 38 publications

(41 citation statements)

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“…In other studies, we found that forced expression of Survivin in human melanocytes in vitro conferred protection against UV-induced apoptosis, reducing both caspase activation and mitochondrial AIF release (38). Here, constitutive Survivin expression in melanocytes did not cause melanocyte hyperplasia, or affect melanocyte localization or melanin production, as indicated by normal histology, PEP8 staining, and pigmentation of the skin and hair in Dct-Survivin mice.…”

Section: Discussionmentioning

confidence: 79%

Melanocyte Expression of Survivin Promotes Development and Metastasis of UV-Induced Melanoma in HGF-Transgenic Mice

et al. 2007

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We previously found the apoptosis inhibitor Survivin to be expressed in melanocytic nevi and melanoma but not in normal melanocytes. To investigate the role of Survivin in melanoma development and progression, we examined the consequences of forced Survivin expression in melanocytes in vivo. Transgenic (Tg) mouse lines (Dct-Survivin) were generated with melanocyte-specific expression of Survivin, and melanocytes grown from Dct-Survivin mice expressed Survivin. Dct-Survivin melanocytes exhibited decreased susceptibility to UV-induced apoptosis but no difference in proliferative capacity compared with melanocytes derived from non-Tg littermates. Induction of nevi in Dct-Survivin and non-Tg mice by topical application of 7,12-dimethylbenz (a)anthracene did not reveal significant differences in lesion onset (median, 10 weeks) or density (4 lesions per mouse after 15 weeks). Dct-Survivin mice were bred with melanomaprone MH19/HGF-B6 Tg mice, and all progeny expressing either individual, neither, or both (Survivin/HGF) transgenes were UV-treated as neonates and then monitored for 43 weeks. Melanocytes in neonatal Survivin + /HGF + mouse skin were less susceptible to UV-induced apoptosis than those from Survivin À /HGF + mice. Onset of melanocytic tumors was earlier (median, 18 versus 24 weeks; P = 0.01, log-rank test), and overall tumor density was greater (7.7 versus 5.2 tumors per mouse; P = 0.04) in Survivin + /HGF + compared with Survivin À /HGF + mice. Strikingly, melanomas arising in Survivin + /HGF + mice showed a greater tendency for lymph node (35% versus 0%; P = 0.04) and lung (53% versus 22%) metastasis and lower rates of spontaneous apoptosis than those in Survivin À /HGF + mice. These studies show a role for Survivin in promoting both early and late events of UV-induced melanoma development in vivo. [Cancer Res 2007;67(11):5172-8]

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Section: Discussionmentioning

confidence: 79%

Melanocyte Expression of Survivin Promotes Development and Metastasis of UV-Induced Melanoma in HGF-Transgenic Mice

et al. 2007

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“…45 Until now, only AIF has been reported to be involved in caspase-independent apoptosis induced by cisplatin. 19,30 AIF was detected from other HNSCC cells, HN3, (data not shown) which is sensitive to cisplatin treatment, 26,32 and it is possible that AIF plays roles in caspase-independent apoptosis in cisplatin-treated HN3 cells. However, expression level of AIF was undetectable in HN4 cells and, thus, was not involved in cisplatininduced caspase-independent apoptosis of HN4 cells.…”

Section: Discussionmentioning

confidence: 99%

“…[19][20][21][22][23] Upon release from mitochondria, AIF and EndoG translocate to the nucleus where they cause DNA fragmentation, 16,17 provoking apoptosis in a caspase-independent manner. 24,25 Cisplatin also has been shown to induce apoptosis through the mitochondrial release of proapoptotic molecules, including cytochrome c, [26][27][28] Omi/HtrA2, 29 Smac/Diablo, 30,31 and AIF. 19,30 However, the mechanisms by which cisplatin initiates apoptosis in cancer cells are not completely understood.…”

Section: Introductionmentioning

confidence: 99%

“…24,25 Cisplatin also has been shown to induce apoptosis through the mitochondrial release of proapoptotic molecules, including cytochrome c, [26][27][28] Omi/HtrA2, 29 Smac/Diablo, 30,31 and AIF. 19,30 However, the mechanisms by which cisplatin initiates apoptosis in cancer cells are not completely understood. Especially, the role of EndoG in the cisplatin-induced apoptosis has not been reported yet.…”

Section: Introductionmentioning

confidence: 99%

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Reactive oxygen species‐dependent EndoG release mediates cisplatin‐induced caspase‐independent apoptosis in human head and neck squamous carcinoma cells

Kim

Lee

Jeong

et al. 2007

Intl Journal of Cancer

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Cisplatin is a chemotherapeutic agent that is widely used to treat cancers such as head and neck squamous cell carcinoma (HNSCC). Previously, we have reported that cisplatin induced an early caspase-dependent apoptosis (8 hr) in a HNSCC cell, HN4. In this study, we examined a late caspase-independent apoptosis as well as an early caspase-dependent apoptosis in cisplatintreated HN4 cells. While z-VAD-fmk, a pan-caspase inhibitor, blocked the caspase activities and protected cells from the early apoptosis, it did not provide protection against delayed apoptosis occurring after extended exposure (16 hr) to cisplatin, suggesting that the delayed apoptotic response in the presence of z-VAD-fmk was caspase-independent. Cisplatin treatment induced reactive oxygen species (ROS) generation, loss of the mitochondrial membrane potential (MMP) and nuclear translocation of endonuclease G (EndoG). Small interfering RNA mediated-knockdown of EndoG significantly protected cells from the delayed apoptosis induced by cisplatin in the presence of z-VAD-fmk. Overexpression of Bcl-2 in HN4 cells prevented loss of MMP, nuclear translocation of EndoG and protected cells from the delayed apoptosis induced by cisplatin in the presence of z-VAD-fmk. Pretreatment with N-acetyl-L-cysteine (NAC), a ROS scavenger, prevented both ROS generation, loss of the MMP and nuclear translocation of EndoG. Together, our data indicate that cisplatin treatment induced ROS-mediated loss of the MMP, and, then, the nuclear translocation of EndoG, which played a crucial role in caspase-independent apoptosis of HN4 cells in the presence of z-VAD-fmk. This is the first report about the involvement of EndoG in cisplatin-induced caspase-independent apoptosis of cells. ' 2007 Wiley-Liss, Inc.

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“…43 TFPI-2 expression was found to be induced by UVB, which is one of the most common causes of malignant melanomas and also induces apoptosis. 44 This suggested that TFPI-2 could have a tumor-suppressive function and exert it through its roles in responding to cellular stresses, including induction of apoptosis. 27 In the screening process of silenced genes, 2 genes (ADFP and MT1K) were found to be expressed even in melanoma cell lines with complete methylation.…”

Section: Discussionmentioning

confidence: 99%

Silencing of tissue factor pathway inhibitor‐2 gene in malignant melanomas

Nobeyama

Okochi‐Takada

Furuta

et al. 2007

Intl Journal of Cancer

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To identify tumor-suppressor genes inactivated by aberrant methylation of promoter CpG islands (CGIs) in human malignant melanomas, genes upregulated by treatment of cells with a demethylating agent, 5-aza-2 0 -deoxycytidine (5-aza-dC), were searched for using oligonucleotide microarrays in melanoma cell lines, HMV-I, MeWo and WM-115. Seventy-nine known genes with CGIs were identified as being upregulated (16-fold), and 18 of them had methylation of their putative promoter CGIs in 1 or more of 8 melanoma cell lines. Among the 18 genes, TFPI-2, which is involved in repression of the invasive potential of malignant melanomas, was further analyzed. Its expression was repressed in a melanoma cell line with its complete methylation, and was restored by 5-aza-dC treatment. It was unmethylated in cultured neonatal normal epidermal melanocyte, and was induced by ultraviolet B. In surgical melanoma specimens, TFPI-2 methylation was detected in 5 of 17 metastatic site specimens (29%), while it was not detected in 20 primary site specimens (0%) (p 5 0.009). By immunohistochemistry, the 5 specimens with promoter methylation lacked immunoreactivity for TFPI-2. The results showed that TFPI-2 is silenced in human malignant melanomas by methylation of its promoter CGI and suggested that its silencing is involved in melanoma metastasis. ' 2007 Wiley-Liss, Inc.

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Activation of Dual Apoptotic Pathways in Human Melanocytes and Protection by Survivin

Cited by 38 publications

References 50 publications

Melanocyte Expression of Survivin Promotes Development and Metastasis of UV-Induced Melanoma in HGF-Transgenic Mice

Melanocyte Expression of Survivin Promotes Development and Metastasis of UV-Induced Melanoma in HGF-Transgenic Mice

Reactive oxygen species‐dependent EndoG release mediates cisplatin‐induced caspase‐independent apoptosis in human head and neck squamous carcinoma cells

Silencing of tissue factor pathway inhibitor‐2 gene in malignant melanomas

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