3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors reduce human pancreatic cancer cell invasion and metastasis

Kusama, Toshiyuki; Mukai, Mutsuko; Iwasaki, Teruo; Tatsuta, Masaharu; Matsumoto, Yoshirou; Akedo, Hitoshi; Inoue, Masahiro; Nakamura, Hiroyuki

doi:10.1053/gast.2002.31093

Cited by 206 publications

(150 citation statements)

References 37 publications

Supporting

Mentioning

142

Contrasting

Unclassified

Order By: Relevance

“…Statins reduced endothelial leukocyte adhesion molecule E-selectin (Nubel et al 2004) and matrix metalloproteinase-9 expression (Wang et al 2000). Fluvastatin and lovastatin inhibited liver tumorigenesis and liver metastasis in pancreatic cancer cells (Kusama et al 2002) and atorvastatin decreased melanoma cell metastasis (Collisson et al 2003). Several epidemiological (Downs et al 1998;Blais et al 2000;Poynter et al 2005;Shannon et al 2005) and clinical studies (Kawata et al 2001;Minden et al 2001;Katz et al 2005) have demonstrated the antitumor potential of statins in various cancer types.…”

Section: Introductionmentioning

confidence: 99%

Antitumor effects of atorvastatin in the chemoprevention of rat mammary carcinogenesis

et al. 2011

View full text Add to dashboard Cite

Epidemiological studies indicate that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, play a role in inhibition of several human neoplasia including breast cancer. In this study, chemopreventive effects of atorvastatin in N-methyl-N-nitrosourea-induced mammary carcinogenesis in female rats were evaluated. Atorvastatin was administered in the diet at two concentrations: 10 mg/kg (ATOR 10) and 100 mg/kg (ATOR 100). Atorvastatin treatment began 8 days prior to carcinogen administration and subsequently continued for 15 weeks till the end of the experiment. Atorvastatin at a higher dose suppressed tumor frequency by 80.5% (P = 0.0008) and tumor incidence by 49.5% (P = 0.015), and extended latency period by 14 days (P = 0.076) when compared to the control group. Atorvastatin at a lower dose did not significantly alter tumor parameters in comparison with the control group. In the specimens of mammary tumors, atorvastatin (in the ATOR 100 group) significantly decreased mRNA expression of Bcl-2 gene but non-significantly increased Bax mRNA expression compared to control group. Atorvastatin administration did not alter serum concentration of triacylglycerols, total cholesterol, and LDL cholesterol in comparison with controls. This study is the first report on tumor suppressive effect of atorvastatin in rat mammary carcinogenesis.

show abstract

Section: Introductionmentioning

confidence: 99%

Antitumor effects of atorvastatin in the chemoprevention of rat mammary carcinogenesis

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Some reports have shown that the negative effect of statins on tumour cell proliferation is potentially caused by a block in the G1-S transition in the cell cycle, attributable to increases in p21 WAF1/CIP1 and p27 KIP1 , by effects on Rho family GTPase(s) (Hirai et al, 1997;Lee et al, 1998). Delocalization of RhoA from the cell membrane by statins also reduced invasion of human pancreatic cell lines (Kusama et al, 2001). Various reports have claimed that Ras inactivation by statins is not the main target of the drugs in their effects on proliferation and apoptosis, although the main line of evidence for this hypothesis is rather indirect, since it involved reversal of the effects of statins by exogenously added lipids (Chan et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Potent inhibition of small-cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling

Pardo²,

et al. 2005

View full text Add to dashboard Cite

The impact of the 3-hydroxy-3methylglutaryl CoA reductase inhibitor simvastatin on human small-cell lung cancer (SCLC) cell growth and survival was investigated. Simvastatin profoundly impaired basal and growth factorstimulated SCLC cell growth in vitro and induced apoptosis. SCLC cells treated with simvastatin were sensitized to the effects of the chemotherapeutic agent etoposide. Moreover, SCLC tumour growth in vivo was inhibited by simvastatin. These responses correlated with the inhibition of stem cell factor (SCF)-stimulated activation of extracellular signal-regulated kinase (Erk), protein kinase B (PKB) and ribosomal S6 kinase by simvastatin. Constitutive activation of the Erk pathway was sufficient to rescue SCLC cell from the effects of simvastatin. The drug did not directly affect activation of c-Kit or its localization to lipid rafts, but in addition to its ability to block Ras membrane localization, it selectively downregulated H-Ras protein levels at the post-translational level. Downregulation of either H-or K-Ras by RNA interference (RNAi) did not impair Erk activation by growth factors, whereas an RNAi specific for N-Ras inhibited activation of Erk, PKB and SCLC cell growth. Together our data demonstrate that inhibiting Ras signalling with simvastatin potently disrupts growth and survival in human SCLC cells.

show abstract

“…Although 22 members of the Rho-GTPase family have been identified, it is the activation of the Rho subfamily that is principally responsible for the assembly of the contractile actomyosin machinery necessary for most types of cell motility (4). Inhibition of Rho or its effector Rho-kinase (ROCK) significantly compromises cellular migration and invasiveness (5)(6)(7)(8)(9)(10), and increased expression͞activation of Rho and its isoforms has been found in many types of cancers (11)(12)(13)(14). A recently discovered mechanism for activating Rho in epithelial cells involves the tuberous sclerosis complex 2 gene product, TSC2 (15).…”

mentioning

confidence: 99%

Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2

Hong

Radisky

Nelson

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

184

150

View full text Add to dashboard Cite

Akt1 is frequently up-regulated in human tumors and has been shown to accelerate cell proliferation and to suppress programmed cell death; consequently, inhibition of the activity of Akt1 has been seen as an attractive target for therapeutic intervention. Paradoxically, hyperactivation of the Akt1 oncogene can also prevent the invasive behavior that underlies progression to metastasis. Here we show that overexpression of activated myr-Akt1 in human breast cancer cells phosphorylates and thereby targets the tumor suppressor tuberous sclerosis complex 2 (TSC2) for degradation, leading to reduced Rho-GTPase activity, decreased actin stress fibers and focal adhesions, and reduced motility and invasion. Overexpression of TSC2 rescues the migration phenotype of myrAkt1-expressing tumor cells, and high levels of TSC2 in breast cancer patients correlate with increased metastasis and reduced survival. These data indicate that the functional properties of genes designated as oncogenes or tumor suppressor genes depend on the context of the cell type and the tissues studied, and suggest the need for caution in designing therapies targeting the function of individual genes in epithelial tissues.metastasis ͉ oncogene ͉ tumor suppressor

show abstract

3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors reduce human pancreatic cancer cell invasion and metastasis

Cited by 206 publications

References 37 publications

Antitumor effects of atorvastatin in the chemoprevention of rat mammary carcinogenesis

Antitumor effects of atorvastatin in the chemoprevention of rat mammary carcinogenesis

Potent inhibition of small-cell lung cancer cell growth by simvastatin reveals selective functions of Ras isoforms in growth factor signalling

Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2

Contact Info

Product

Resources

About