p66<sup>Shc</sup> protein is upregulated by steroid hormones in hormone‐sensitive cancer cells and in primary prostate carcinomas

Lee, Ming Shyue; Igawa, Tsukasa; Chen, Siu Ju; Bemmel, Dana van; Lin, Jamie S.; Lin, Fen Fen; Johansson, Sonny L.; Christman, Judith K.; Lin, Ming Fong

doi:10.1002/ijc.11621

Cited by 42 publications

(79 citation statements)

References 35 publications

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“…To the best of our knowledge, this is the first report that p66Shc-ROS pathway mediates early androgenic cell proliferation in androgen-sensitive prostate cancer cells, which is independent of AR-dependent gene expression, such as PSA. Data obtained from this study, thus, provide a molecular explanation for the clinical observations on increased p66Shc and ROS production in archival prostate cancer specimens (Lee et al, 2004a;Lim et al, 2005). In parallel, increased levels of H 2 O 2 -producing enzymes, such as Nox1 and SOD, are also noticed in prostate cancer specimens (Kuruma et al, 2005;Lim et al, 2005).…”

Section: Discussionsupporting

confidence: 63%

“…p66Shc regulates DHT-induced proliferation in prostate cancer cells Previous studies indicated that p66Shc, which increases intracellular ROS levels, is elevated in DHT-treated prostate cancer cells (Lee et al, 2004a; Figure 3a). Furthermore, semiquantitative analyses of the blots indicated a significantly higher level of p66Shc protein from 8 h of DHT treatment (Po0.05) (Supplementary Figure 1) prior to increase in ROS production (16 h), as indicated by an dichlorofluorescein diacetate (DCF-DA) fluorescence (Figure 3b), and the stimulation of cell proliferation, as indicated by the increase in Cyclin D1 level (24 h) (Figure 3a), the percentage of cells at S-phase (24 h) ( Figure 3c) and cell number (48 h) (Figure 3d).…”

Section: Resultsmentioning

confidence: 91%

“…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. Thus, the biological outcome of p66Shc signaling might be diverse in different cell types.…”

Section: Introductionmentioning

confidence: 97%

“…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: 98%

“…However, a negative correlation between p66Shc and tumorigenicity in breast cancer tissues has been reported recently, and further studies are thus required to define its role in breast carcinogenesis (Stevenson and Frackelton, 1998;Davol et al, 2003). 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).…”

Section: Introductionmentioning

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: Discussionsupporting

confidence: 63%

Section: Resultsmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2008

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Measuring p66Shc Signaling Pathway Activation and Mitochondrial Translocation in Cultured Cells

et al. 2015

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The adaptor protein p66Shc links membrane receptors to intracellular signaling pathways, with downstream consequences on mitochondrial metabolism and reactive oxygen species production. Moreover, p66Shc has also been implicated in cancer development, progression, and metastasis. Increased phosphorylation of serine 36 residue of p66Shc very often correlates with oxidative stress-associated pathologies. The pro-oxidative role of p66Shc also appears to be involved in chemical toxicity, being an important component of stress responses triggered by xenobiotics. Here, we present a protocol that can be used: (a) for isolation of mitochondrial, cytosolic, and mitochondrial-associated membrane fractions from adherent cells lines; (b) to perform p66Shc detection with specific antibodies in order to monitor its translocation between different cellular compartments in response to the oxidative stress; and (c) to modulate the p66Shc pathway with the use of pharmacological approaches or gene-silencing methods.

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D,L‐sulforaphane‐induced apoptosis in human breast cancer cells is regulated by the adapter protein p66^Shc

Sakao

Singh

2012

J of Cellular Biochemistry

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Cancer chemopreventive response to D,L-sulforaphane (SFN), a synthetic racemic analogue of broccoli constituent L-sulforaphane, is partly attributable to apoptosis induction, but the mechanism of cell death is not fully understood. The present study demonstrates a critical role for adapter protein p66Shc in SFN -induced apoptosis. Immortalized mouse embryonic fibroblasts (MEF) derived from p66shc knockout mice were significantly more resistant to SFN-induced apoptosis, collapse of mitochondrial membrane potential, and reactive oxygen species (ROS) production compared with MEF obtained from the wild-type mice. Notably, a spontaneously immortalized and non-tumorigenic human mammary epithelial cell line (MCF-10A) was resistant to SFN-induced ROS production and apoptosis. Stable overexpression of manganese superoxide dismutase in MCF-7 and MDA-MB-231 human breast cancer cells conferred near complete protection against SFN-induced apoptosis and mitochondrial membrane potential collapse. SFN treatment resulted in increased S36 phosphorylation and mitochondrial translocation of p66shc in MDA-MB-231 and MCF-7 cells, and SFN-induced apoptosis was significantly attenuated by RNA interference of p66shcin both cells. SFN-treated MDA-MB-231 and MCF-7 cells also exhibited a marked decrease in protein level of peptidyl prolyl isomerase (Pin1), which is implicated in mitochondrial translocation of p66shc. However, stable overexpression of Pin1 failed to alter proapoptotic response to SFN at least in MCF-7 cells. Finally, SFN-induced S36 phosphorylation of p66Shc was mediated by protein kinase Cβ (PKCβ), and pharmacological inhibition of PKCβ significantly inhibited apoptotic cell death resulting from SFN exposure. In conclusion, the present study provides new insight into the mechanism of SFN-induced apoptosis involving PKCβ-mediated S36 phosphorylation of p66shc.

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p66^Shc protein is upregulated by steroid hormones in hormone‐sensitive cancer cells and in primary prostate carcinomas

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Cited by 42 publications

References 35 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

Measuring p66Shc Signaling Pathway Activation and Mitochondrial Translocation in Cultured Cells

D,L‐sulforaphane‐induced apoptosis in human breast cancer cells is regulated by the adapter protein p66^Shc

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p66Shc protein is upregulated by steroid hormones in hormone‐sensitive cancer cells and in primary prostate carcinomas

Abstract: Members of

Cited by 42 publications

References 35 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

Measuring p66Shc Signaling Pathway Activation and Mitochondrial Translocation in Cultured Cells

D,L‐sulforaphane‐induced apoptosis in human breast cancer cells is regulated by the adapter protein p66Shc

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p66^Shc protein is upregulated by steroid hormones in hormone‐sensitive cancer cells and in primary prostate carcinomas

D,L‐sulforaphane‐induced apoptosis in human breast cancer cells is regulated by the adapter protein p66^Shc