A role for SIRT1 in cell growth and chemoresistance in prostate cancer PC3 and DU145 cells

Kojima, Keitaro; Ohhashi, Riyako; Fujita, Yasunori; Hamada, Naoki; Akao, Yukihiro; Nozawa, Yoshinori; Deguchi, Takashi; Ito, Masafumi

doi:10.1016/j.bbrc.2008.06.045

Cited by 153 publications

(126 citation statements)

References 17 publications

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“…H 2 O 2 moderately reduced the cellular NAD þ level, but SIRT1 knockdown did not result in further reduction (Figure 6c). Our results are in-line with previous findings that SIRT1 is important for prostate cancer-cell survival and growth (Kojima et al, 2008;Jung-Hynes et al, 2009). We next characterized SIRT1 functions downstream of NAMPT.…”

Section: Nampt Is Overexpressed In Human Prostate Cancersupporting

confidence: 93%

“…SIRT1 is overexpressed in primary human prostate cancer and mouse models of prostate cancer (Huffman et al, 2007;Jung-Hynes et al, 2009). However, roles of SIRT1 in prostate cancer remain controversial as two groups show that SIRT1 promotes prostate cancer cell growth and survival (Kojima et al, 2008;Jung-Hynes et al, 2009) whereas the other two groups show the opposite effect (Fu et al, 2006;Dai et al, 2007). To examine roles of SIRT1 in prostate cancer cells, we first treated LNCaP and PC3 cells with a sirtuin inhibitor, sirtinol (Grozinger et al, 2001).…”

Section: Nampt Is Overexpressed In Human Prostate Cancermentioning

confidence: 99%

“…Inhibition of SIRT1 suppresses growth and promotes apoptosis in human cancer cells (Luo et al, 2001;Vaziri et al, 2001;Chu et al, 2005;Ford et al, 2005;Ota et al, 2006;Kojima et al, 2008;Jung-Hynes et al, 2009), but has little impact on the survival of normal cells (Ford et al, 2005;Jung-Hynes et al, 2009). Consistently, loss of tumor suppressor gene p53 results in increase of SIRT1 expression (Nemoto et al, 2004), and we have shown that the epigenetically-regulated tumor suppressor HIC1 (hypermethylated in cancer 1) directly represses SIRT1 expression .…”

Section: Introductionmentioning

confidence: 99%

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NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

et al. 2010

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Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in regenerating nicotinamide adenine dinucleotide (NAD þ ) from nicotinamide in mammals. NAMPT has crucial roles for many cellular functions by regulating NAD þ -dependent SIRT1 deacetylase. However, roles of NAMPT in cancer are poorly defined. In this study, we show that NAMPT is prominently overexpressed in human prostate cancer cells along with SIRT1. Elevation of NAMPT expression occurs early for the prostate neoplasia. Inhibition of NAMPT significantly suppresses cell growth in culture, soft agar colony formation, cell invasion and growth of xenografted prostate cancer cells in mice. NAMPT knockdown sensitizes prostate cancer cells to oxidative stress caused by H 2 O 2 or chemotherapeutic treatment. Overexpression of NAMPT increases prostate cancer cell resistance to oxidative stress, which is partially blocked by SIRT1 knockdown. We demonstrate that in addition to modulating SIRT1 functions, the NAMPT inhibition reduces forkhead box, class 'O' (FOXO)3a protein expression and its downstream anti-oxidant genes catalase and manganese superoxide dismutase. Our results suggest important roles of concomitant upregulation of NAMPT and SIRT1 along with increased FOXO3a protein level for prostate carcinogenesis and their contribution to oxidative stress resistance of prostate cancer cells. These findings may have implications for exploring the NAMPT pathway for prostate cancer prevention and treatment.

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Section: Nampt Is Overexpressed In Human Prostate Cancersupporting

confidence: 93%

Section: Nampt Is Overexpressed In Human Prostate Cancermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

et al. 2010

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“…Inhibition of SIRT1 in PC3 or DU145 cells suppressed cell proliferation and sensitized cells to camptothecin and cisplatin (Kojima et al, 2008). But the underlying mechanism was not clear.…”

Section: Scf-skp2 Ubiquitinates Foxo3mentioning

confidence: 99%

“…FOXO3 levels are reversely correlated with SIRT1 and Skp2 levels in prostate cancer cell lines It was reported that SIRT1 levels were markedly upregulated in PC3 and DU145 malignant prostate cell lines compared with normal human prostate epithelial cells (PrECs) (Kojima et al, 2008). Inhibition of SIRT1 in PC3 or DU145 cells suppressed cell proliferation and sensitized cells to camptothecin and cisplatin (Kojima et al, 2008).…”

Section: Scf-skp2 Ubiquitinates Foxo3mentioning

confidence: 99%

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation

et al. 2011

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Sirtuin deacetylases and FOXO (Forkhead box, class O) transcription factors have important roles in many biological pathways, including cancer development. SIRT1 and SIRT2 deacetylate FOXO factors to regulate FOXO function. Because acetylation and ubiquitination both modify the e-amino group of lysine residues, we investigated whether FOXO3 deacetylation by SIRT1 or SIRT2 facilitates FOXO3 ubiquitination and subsequent proteasomal degradation. We found that SIRT1 and SIRT2 promote FOXO3 poly-ubiquitination and degradation. Proteasome-inhibitor treatment prevented sirtuininduced FOXO3 degradation, indicating that this process is proteasome dependent. In addition, we demonstrated that E3 ubiquitin ligase subunit Skp2 binds preferentially to deacetylated FOXO3. Overexpression of Skp2 caused poly-ubiquitination of FOXO3 and degradation, whereas knockdown of Skp2 increased the amount of FOXO3 protein. We also present evidence that SCF-Skp2 ubiquitinates FOXO3 directly in vitro. Furthermore, mutating four known acetylated lysine residues (K242, K259, K290 and K569) of FOXO3 into arginines to mimic deacetylated FOXO3 resulted in enhanced Skp2 binding but with inhibition of FOXO3 ubiquitination; this suggests that some or all of these four lysine residues are likely the sites for ubiquitination. In the livers of mice deficient in SIRT1, we detected increased expression of FOXO3, indicating SIRT1 regulates FOXO3 protein levels in vivo. Furthermore, we found that the elevation of SIRT1 and Skp2 expression in malignant PC3 and DU145 prostate cells is responsible for the downregulation of FOXO3 protein levels in these cells. Taken together, our data support the notion that deacetylation of FOXO3 by SIRT1 or SIRT2 facilitates Skp2-mediated FOXO3 poly-ubiquitination and proteasomal degradation.

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Sirtuins as Drug Targets

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2019

Epigenetic Drug Discovery

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A role for SIRT1 in cell growth and chemoresistance in prostate cancer PC3 and DU145 cells

Cited by 153 publications

References 17 publications

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

NAMPT overexpression in prostate cancer and its contribution to tumor cell survival and stress response

Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation

Sirtuins as Drug Targets

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