Breast cancer
Colorectal
Carcinomas
Longevity
2007/8-1/33
Ann Surg Oncol. 2007
Jul 26; [Epub ahead of print] Bauer
TW, Fan
F, Liu
W, Camp
ER, Yang
A, Somcio RJ, Bucana CD, Singh
R, Ellis
LM. Department of Surgical
Oncology, The University of Texas M. D. Anderson Cancer Center, 1515
Holcombe Blvd., Houston, TX, 77030, USA. BACKGROUND: Colorectal
carcinomas (CRC) express high levels of insulin-like growth factor-I/II
(IGF-I/II) and the receptor (IGF-IR). We hypothesized that selective inhibition
of IGF-IR would inhibit hepatic growth of human CRC in mice. METHODS: Human
CRC cells were treated in vitro with anti-IGF-IR monoclonal antibody ( PMID: 17653802 [PubMed
- as supplied by publisher] Diabetologia.
2007 Dec;50(12):2534-2543. Epub
2007 Sep 18. Eckardt K, May
C, Koenen M, Eckel J. Institute of Clinical
Biochemistry and Pathobiochemistry, AIMS/HYPOTHESIS: Mitogenic activity of insulin and insulin analogues and
the involvement of the IGF-1 receptor (IGF-1R) is still a controversial
issue. We compared levels of the proteins IGF-1R and insulin receptor (InsR) in fibroblasts and smooth muscle cells from
healthy donors and assessed the downstream signalling
and growth-promoting activity of insulin and insulin analogues. METHODS:
DNA synthesis was monitored in human fibroblasts and coronary artery smooth
muscle cells. Using small interfering RNAs, the
levels of IGF-1 and InsR were reduced by 95 and
75%, respectively. RESULTS: Enhanced mitogenic
potency of insulin and insulin analogues was observed which correlated with
increased levels of IGF-1R and/or IRS-1. A reduction in the IGF-1R level
significantly blunted stimulation of Akt phosphorylation by IGF-1, AspB10 and glargine by 72, 58 and 40%, respectively. Akt phosphorylation in
response to insulin remained unaffected. Silencing of InsR
did not significantly alter Akt phosphorylation in response to IGF-1, AspB10 and glargine. IGF-1R knockdown reduced the stimulation of
DNA synthesis in response to IGF-1 and glargine
to a level identical to that produced by insulin.
CONCLUSIONS/INTERPRETATION: These data show a prominent role of IGF-1R/Akt signalling in mediating the mitogenic
effects of insulin analogues. Regular insulin stimulates DNA synthesis by
exclusively activating InsR, whereas insulin
analogues mainly signal through IGF-1R. It is suggested that
inter-individual differences in the levels of proteins of the IGF-1R system
may function as a critical determinant of the mitogenic
potency of insulin analogues. PMID: 17898992 [PubMed
- as supplied by publisher] Breast
Cancer Res Treat. 2006 Oct;99(3):275-88. Epub 2006 Jun
5. Chong YM, Colston K, Jiang WG, Sharma
AK, Mokbel K. Department
of Cellular & Molecular Medicine, AIMS: Previous studies have
shown that oestrogen and Insulin-like Growth
Factor-1 (IGF-1) act synergistically and cross-stimulatory while the oestrogen receptor (ER) and IGF-1R downstream signalling pathways interact at many levels. We
investigate the relationship between the ER, and IGF-1R and their ligands in a series of human breast cancer tissue and
adjacent non-cancerous tissue (ANCT). METHODS: A series of 139 pairs of breast
cancer tissue and ANCT were obtained and divided into ER positive and ER
negative groups based on tumour ER alpha immunostaining. All samples were processed for
real-time quantitative-PCR to measure IGF-1, IGF-1R, ER alpha, STS and
Cyp-19 mRNA levels. In addition, ER positive MCF-7 and ER negative
MDA-MB-231 cell lines were treated separately with IGF-1 and an IGF-1R
inhibitor called Tyrphostin AG1024 to see the
effects of stimulating and inhibiting the IGF-1R. MCF-7 cell line was also
treated with 4-hydroxytamoxifen. The mRNA levels of IGF-1, IGF-1R, ER
alpha, STS and Cyp-19 of treated cell lines were measured and compared to
those of non-treated controls. Data generated was normalised
to Cytokeratin-19 mRNA levels. RESULTS: IGF-1R expression was higher in tumour tissue compared to ANCT (P = 0.038) while IGF-1
expression was marginally higher in ANCT compared to tumour
tissue only in the ER positive samples (P = 0.098). ER positive tumours had a higher expression of IGF-1 compared to ER
negative tumours (P = 0.001) while IGF-1R, STS
and Cyp-19 expression were higher in ER negative tumours
(P = 0.000, 0.000 and 0.006 respectively). There was no difference in STS
or Cyp-19 expression in tumours or ANCT. Using
Spearman's Correlation test, IGF-1 positively correlated with STS, Cyp-19
and ER alpha in ER positive and negative groups (Coefficient = +0.497,
+0.662 and +0.651 respectively, P = 0.000 in all). IGF-1R correlated with
IGF-1, STS, Cyp-19 and ER alpha only in the ER negative tumours
(Coefficient = +0.620, +0.394, +0.692 and +0.662 respectively, P = 0.000,
0.012, 0.000 and 0.000 respectively). In cell lines, IGF-1 treatment led to
an increase in the mean expression of IGF-1, IGF-1R, STS and Cyp-19 in both
cell lines while ER alpha expression increased only in MCF-7. IGF-1R
inhibition caused a decrease in expression of all five genes in MDA-MB-231
but not in the MCF-7 cell line. Treatment with 4-hydroxytamoxifen caused a
decrease in expression of all five genes. CONCLUSIONS: IGF-1R is
over-expressed in malignant tissue. IGF-1 is expressed at higher levels in
ER positive tumours probably as a result of oestrogen stimulation while IGF-1R expression is higher
in ER negative samples as an adaptation to lower local IGF-1 levels. An
IGF-1 paracrine relationship may exist between tumour and ANCT but for STS and Cyp-19, there may be an
autocrine-paracrine relationship. The IGF-1 ligand-receptor system is an important regulator of oestrogen production while oestrogen
may be involved in stimulating IGF-1 expression. The expression of oestrogen synthesising
enzymes is higher in ER negative breast cancers which may be due to the
lack of oestrogen negative feedback or
contribution from the overexpression of IGF-1R. PMID: 16752221 [PubMed
- indexed for MEDLINE] Breast
Cancer Res Treat. 2006 Oct;99(3):323-31. Epub 2006 Jun
5. Fan
J, McKean-Cowdin R, Bernstein
L, Stanczyk FZ, Li
AX, Ballard-Barbash R, McTiernan A, Baumgartner
R, Gilliland
F. Integrated
Substance Abuse Programs, Neuropsychiatric
Institute, Insulin receptor substrate-1
(IRS-1) is a key downstream signaling molecule common to both the insulin
and IGF signaling pathways that can interact with the estrogen pathway to
regulate breast cell growth. We investigated whether a putative functional
variant for IRS-1 (G972R) influences circulating levels of sex hormones,
sex hormone binding globulin (SHBG), C-peptide, and insulin-like growth
factor 1 (IGF-1) levels among post-menopausal African-American and
non-Hispanic white breast cancer patients enrolled in the Health, Eating,
Activity, and Lifestyle (HEAL) Study. Circulating levels of sex hormones
and growth factors can influence breast cancer recurrence and survival.
Serum estrone, estradiol,
testosterone, SHBG, IGF-1 and C-peptide were measured in 468 patients at
30+ months post diagnosis. Non-protein bound hormone levels (free estradiol, free testosterone) were calculated. In
African-American patients, the IRS-1 variant was associated with increased
serum levels of estrone (p = 0.02), free estradiol (p = 0.04), total testosterone (p = 0.04),
free testosterone (p = 0.006) and decreased levels of sex hormone-binding
globulin (p = 0.02). No association was present for white patients. Our
findings provide suggestive evidence that IRS-1 G972R variant may be associated
with circulating levels of sex hormones and SHBG in African American breast
cancer survivors. PMID: 16752222 [PubMed
- indexed for MEDLINE] IGF-1 protects cardiac myocytes from hyperosmotic stress-induced apoptosis via CREB. J
Lab Clin Med. 2006 May;147(5):234-41.
Targeting of Insulin-like
Growth Factor-I Receptor with a Monoclonal Antibody Inhibits Growth of
Hepatic Metastases from Human Colon Carcinoma in Mice.
IGF-1 receptor signalling
determines the mitogenic potency of insulin
analogues in human smooth muscle cells and fibroblasts.
The relationship between the
insulin-like growth factor-1 system and the oestrogen
metabolising enzymes in breast cancer tissue and
its adjacent non-cancerous tissue.
An association between a
common variant (G972R) in the IRS-1 gene and sex hormone levels in post-menopausal
breast cancer survivors.
Maldonado C,
Cea
P, Adasme
T, Collao
A, Diaz-Araya G,
Chiong
M, Lavandero
S.
Departamento de Bioquimica
y Biologia Molecular, Facultad
de Ciencias Quimicas y Farmaceuticas, Universidad de Chile, Santiago, Chile;
Centro FONDAP Estudios Moleculares
de la Celula, Universidad de Chile, Santiago,
Chile.
Hyperosmotic stress stimulates a rapid and
pronounced apoptosis in cardiac myocytes which is
attenuated by insulin-like growth factor-1 (IGF-1). Because in these cells
IGF-1 induces intracellular Ca(2+) increase, we
assessed whether the cyclic AMP response element-binding protein (CREB) is
activated by IGF-1 through Ca(2+)-dependent signalling
pathways. In cultured cardiac myocytes, IGF-1
induced phosphorylation (6.5+/-1.0-fold at 5min),
nuclear translocation (30min post-stimulus) and DNA binding activity of
CREB. IGF-1-induced CREB phosphorylation was
mediated by MEK1/ERK, PI3-K, p38-MAPK, as well as Ca(2+)/calmodulin kinase and calcineurin. Exposure of cardiac myocytes
to hyperosmotic stress (sorbitol
600mOsm) decreased IGF-1-induced CREB activation Moreover,
overexpression of a dominant negative CREB
abolished the anti-apoptotic effects of IGF-1. Our results suggest that
IGF-1 activates CREB through a complex signalling
pathway, and this transcription factor plays an important role in the
anti-apoptotic action of IGF-1 in cultured cardiac myocytes.
PMID: 16168389 [PubMed - as supplied by
publisher]
Coordinate activation of intracellular
signaling pathways by insulin-like growth factor-1 and platelet-derived
growth factor in rat hepatic stellate cells.
Bridle
KR, Li
L, O'neill R, Britton
RS, Bacon
BR.
Division of Gastroenterology and Hepatology,
Saint Louis University Liver Center, Saint Louis University School of
Medicine, St. Louis, Missouri.
Proliferation of activated hepatic stellate cells
(HSC) is an important event in the development of hepatic fibrosis.
Insulin-like growth factor-1 (IGF-1) has been shown to be mitogenic for HSC, but the intracellular signaling
pathways involved have not been fully characterized. Thus, the aims of the
current study were to examine the roles of the extracellular
signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3-K) and p70-S6 kinase (p70-S6-K) signaling pathways in IGF-1- and
platelet-derived growth factor (PDGF)-induced mitogenic
signaling of HSC and to examine the potential crosstalk between these
pathways. Both IGF-1 and PDGF increased ERK, PI3-K and p70-S6-K activity.
When evaluating potential crosstalk between these signaling pathways, we
observed that PI3-K is required for p70-S6-K activation by IGF-1 and PDGF,
and is partially responsible for PDGF-induced ERK activation. PDGF and
IGF-1 also increased the levels of cyclin D1 and phospho-glycogen synthase
kinase-3beta. Coordinate activation of ERK, PI3-K and p70-S6-K is important
for perpetuating the activated state of HSC during fibrogenesis.
PMID: 16697771 [PubMed - in process]