Expression of p66Shc protein correlates with proliferation of human prostate cancer cells

Veeramani, Suresh; Igawa, Tsukasa; Yuan, Ta Chun; Lin, Fen Fen; Lee, Ming Shyue; Lin, Jamie S.; Johansson, Sonny L.; Lin, Ming Fong

doi:10.1038/sj.onc.1208852

Cited by 52 publications

(80 citation statements)

References 34 publications

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“…p66Shc in androgenic growth stimulation of prostate cancer cells S Veeramani et al p66Shc was initially reported as a proapoptotic molecule, as shown in mouse embryo fibroblasts (Migliaccio et al, 1999;Giorgio et al, 2005;Khanday et al, 2006). However, several lines of evidence suggest that p66Shc might mediate growth signals in epithelial cells and carcinomas (Xie and Hung;Lee et al, 2004a;Park et al, 2005;Veeramani et al, 2005;Grossman et al, 2007). In our study, elevated expression of p66Shc in androgen-sensitive prostate cancer cells did not induce significant cell death as clearly evidenced by cell counting (Figure 4), intracellular proapoptotic Bax protein levels and subG1 DNA content (Veeramani S and Lin MF, unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

“…Prostate carcinoma tissues display higher p66Shc protein levels in the cancerous cells than the adjacent non-cancerous cells (Lee et al, 2004a). In prostate cancer cell lines, p66Shc protein level positively correlates with their growth rates (Lee et al, 2004a;Veeramani et al, 2005). Importantly, growth stimulation of prostate, testis and breast cancer cell lines with steroid hormones is accompanied by an increase in p66Shc protein level (Lee et al, 2004a), implying its function in steroid-induced proliferation.…”

Section: Introductionmentioning

confidence: 90%

“…Anti-b-actin antibody, NAC and VES were from Sigma (St Louis, MO, USA). All the other reagents and chemicals used in this study were as described previously Meng and Lin, 1998;Lee et al, 2004a, b;Veeramani et al, 2005).…”

Section: Methodsmentioning

confidence: 99%

“…Charcoal/dextran-treated FBS was purchased from HyClone (Logan, UT, USA). Myc-tagged wild-type p66Shc cDNA was constructed in pcDNA3.1 vector (Veeramani et al, 2005). Mutant p66Shc cDNA, whose tryptophan 134 was mutated to phenylalanine (W134F), was created by site-directed mutagenesis and confirmed by DNA sequencing.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were then exposed to DHT (10 nM) and harvested after various periods of time, as indicated in each experiment. MDA PCa2b cells were cultured in BRFF-HPC1 medium containing 20% FBS, 2 mM glutamine and 50 mg/ml gentamicin (Lee et al, 2004a;Veeramani et al, 2005). For steroid-reduced conditions, BRFF-BMZERO medium containing 15% charcoal/dextran-treated FBS was used.…”

Section: Cell Linesmentioning

confidence: 99%

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Mitochondrial redox signaling by p66Shc is involved in regulating androgenic growth stimulation of human prostate cancer cells

et al. 2008

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p66Shc is shown to negatively regulate the life span in mice through reactive oxygen species (ROS) production. Recent reports, however, revealed that p66Shc protein level is significantly elevated in several human cancer tissues and growth-stimulated carcinoma cells, suggesting a mitogenic and carcinogenic role for p66Shc. In this communication, we demonstrate for the first time that p66Shc mediates androgenic growth signals in androgen-sensitive human prostate cancer cells through mitochondrial ROS production. Growth stimulation of prostate cancer cells with 5a-dihydrotestosterone (DHT) is accompanied by increased p66Shc level and ROS production, which is abolished by antioxidant treatments. However, antioxidant treatments do not affect the transcriptional activity of androgen receptor (AR) as observed by its inability to block DHTinduced prostate-specific antigen expression, an AR-dependent correlate of prostate cancer progression. Elevated expression of p66Shc by cDNA transfection increases the basal cell proliferation and, thus, reduces additional DHTinduced cell proliferation. Furthermore, DHT increases the translocation of p66Shc into mitochondria and its interaction with cytochrome c. Conversely, both redox-negative p66Shc mutant (W134F), which is deficient in cytochrome c interaction, and p66Shc small interfering RNA decrease DHT-induced cell proliferation. These results collectively reveal a novel role for p66Shc-ROS pathway in androgeninduced prostate cancer cell proliferation and, thus, may play a role in early prostate carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Cell Linesmentioning

confidence: 99%

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Mitochondrial redox signaling by p66Shc is involved in regulating androgenic growth stimulation of human prostate cancer cells

et al. 2008

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Pathway sensitivity analysis for detecting pro‐proliferation activities of oncogenes and tumor suppressors of epidermal growth factor receptor‐extracellular signal‐regulated protein kinase pathway at altered protein levels

Ung

Xiao

et al. 2009

Cancer

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BACKGROUND: Mathematic models and sensitivity analyses of biologic pathways have been used for exploring the dynamics and for detecting the key components of signaling pathways. METHODS: The authors previously developed a mathematic model of the epidermal growth factor receptor‐extracellular signal‐regulated protein kinase (EGFR‐ERK) pathway using ordinary differential equations from existing EGFR‐ERK pathway models. By using prolonged ERK activation as an indicator that may lead to cell proliferation under certain circumstances, in the current study, a pathway sensitivity analysis was performed to test its capability of detecting pro‐proliferative activities through altered protein levels to examine the effects on ERK activation. RESULTS: The analysis revealed that 12 of 20 oncoproteins and 4 of 5 tumor suppressors were detected, consistent with reported experimental works. Because pathway dynamics depend on many factors, some of which were not included in the current models, failure to detect all known oncogenes and tumor suppressors can be because of the failure to include relevant crosstalk to other pathway components. CONCLUSIONS: Overall, the current results indicated that pathway sensitivity analysis is a useful approach for detecting and distinguishing pro‐proliferation activities of oncoproteins and suppressed proliferative activities of tumor suppressors at altered protein levels at least in the EGFR‐ERK model. Cancer 2009. © 2009 American Cancer Society.

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p66Shc longevity protein regulates the proliferation of human ovarian cancer cells

Muniyan

Chou

Tsai

et al. 2014

Molecular Carcinogenesis

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p66Shc functions as a longevity protein in murine and exhibits oxidase activity in regulating diverse biological activities. In this study, we investigated the role of p66Shc protein in regulating ovarian cancer (OCa) cell proliferation. Among three cell lines examined, the slowest growing OVCAR-3 cells have the lowest level of p66Shc protein. Transient transfection with p66Shc cDNA expression vector in OVCAR-3 cells increases cell proliferation. Conversely, knock-down of p66Shc by shRNA in rapidly growing SKOV-3 cells results in decreased cell growth. In estrogen (E2)-treated CaOV-3 cells, elevated p66Shc protein level correlates with ROS level, ErbB-2 and ERK/MAPK activation, and cell proliferation. Further, the E2-stimulated proliferation of CaOV-3 cells was blocked by antioxidants and ErbB-2 inhibitor. Additionally, in E2-stimulated cells, the tartrate-sensitive, but not the tartrate-resistant, phosphatase activity decreases; concurrently, the tyrosine phosphorylation of ErbB-2 increases. Conversely, inhibition of phosphatase activity by L(+)-tartrate treatment increases p66Shc protein level, ErbB-2 tyrosine phosphorylation, ERK/MAPK activation and cell growth. Further, inhibition of the ERK/MAPK pathway by PD98059 blocks E2-induced ERK/MAPK activation and cell proliferation in CaOV-3 cells. Moreover, immunohistochemical analyses showed that the p66Shc protein level was significantly higher in cancerous cells than in non-cancerous cells in archival OCa tissues (n=76; p=0.00037). These data collectively indicate that p66Shc protein plays a critical role in up-regulating OCa progression.

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Expression of p66Shc protein correlates with proliferation of human prostate cancer cells

Cited by 52 publications

References 34 publications

Mitochondrial redox signaling by p66Shc is involved in regulating androgenic growth stimulation of human prostate cancer cells

Mitochondrial redox signaling by p66Shc is involved in regulating androgenic growth stimulation of human prostate cancer cells

Pathway sensitivity analysis for detecting pro‐proliferation activities of oncogenes and tumor suppressors of epidermal growth factor receptor‐extracellular signal‐regulated protein kinase pathway at altered protein levels

p66Shc longevity protein regulates the proliferation of human ovarian cancer cells

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