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DOI: 10.1055/s-0029-1243603
© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York
Insulin Signal Transduction in Normal Cells and its Role in Carcinogenesis
Publikationsverlauf
received 17.11.2009
first decision 17.11.2009
accepted 20.11.2009
Publikationsdatum:
05. Februar 2010 (online)

Abstract
Convincing epidemiological evidence exists for a causal relationship between increased risk of cancer development and progression and type 2 diabetes mellitus as well as obesity. Though the underlying mechanisms remain elusive, in light of the well-described mitogenic actions of insulin, hyperinsulinaemia in the presence of insulin resistance is probably a key factor. In this short review, an overview over the insulin signalling cascade is given paying special attention to the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI 3-K)/mammalian target of rapamycin (mTOR) pathways which are involved in protein synthesis and cell growth.
Key words
mammalian target of rapamycin - MAPK - mitogen-activated protein kinase - mTOR - phosphatidylinositol 3-kinase - PI 3-K - RafRas - small molecule inhibitors - tumorigenesis
References
- 1
Adjei AA, Cohen RB, Franklin W. et al .
Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated
protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced
cancers.
J Clin Oncol.
2008;
26
2139-2146
Reference Ris Wihthout Link
- 2
Alessi DR, James SR, Downes CP. et al .
Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates
and activates protein kinase Balpha.
Curr Biol.
1997;
7
261-269
Reference Ris Wihthout Link
- 3
Baltensperger K, Kozma LM, Cherniack AD. et al .
Binding of the Ras activator son of sevenless to insulin receptor substrate-1 signaling
complexes.
Science.
1993;
260
1950-1952
Reference Ris Wihthout Link
- 4
Burgering BM.
A brief introduction to FOXOlogy.
Oncogene.
2008;
27
2258-2262
Reference Ris Wihthout Link
- 5
Calle EE, Rodriguez C, Walker-Thurmond K. et al .
Overweight, obesity, and mortality from cancer in a prospectively studied cohort of
U.
S. adults. N Engl J Med.
2003;
348
1625-1638
Reference Ris Wihthout Link
- 6
Cheatham B, Kahn CR.
Insulin action and the insulin signaling network.
Endocr Rev.
1995;
16
117-142
Reference Ris Wihthout Link
- 7
Coughlin SS, Calle EE, Teras LR. et al .
Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults.
Am J Epidemiol.
2004;
159
1160-1167
Reference Ris Wihthout Link
- 8
Curatolo P, Bombardieri R, Jozwiak S.
Tuberous sclerosis.
Lancet.
2008;
372
657-668
Reference Ris Wihthout Link
- 9
Cusi K, Maezono K, Osman A. et al .
Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated
signaling in human muscle.
J Clin Invest.
2000;
105
311-320
Reference Ris Wihthout Link
- 10
Davies H, Bignell GR, Cox C. et al .
Mutations of the BRAF gene in human cancer.
Nature.
2002;
417
949-954
Reference Ris Wihthout Link
- 11
Draznin B.
Mitogenic action of insulin: friend, foe or ‘frenemy’?.
Diabetologia.
2009;
Reference Ris Wihthout Link
- 12
Garcia-Martinez JM, Alessi DR.
mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation
of serum- and glucocorticoid-induced protein kinase 1 (SGK1).
Biochem J.
2008;
416
375-385
Reference Ris Wihthout Link
- 13
Han SW, Kim TY, Jeon YK. et al .
Optimization of patient selection for gefitinib in non-small cell lung cancer by combined
analysis of epidermal growth factor receptor mutation, K-ras mutation, and Akt phosphorylation.
Clin Cancer Res.
2006;
12
2538-2544
Reference Ris Wihthout Link
- 14
Hersey P, Bastholt L, Chiarion-Sileni V. et al .
Small molecules and targeted therapies in distant metastatic disease.
Ann Oncol.
2009;
20
((Suppl 6))
vi35-vi40
Reference Ris Wihthout Link
- 15
Hess G, Herbrecht R, Romaguera J. et al .
Phase III study to evaluate temsirolimus compared with investigator's choice therapy
for the treatment of relapsed or refractory mantle cell lymphoma.
J Clin Oncol.
2009;
27
3822-3829
Reference Ris Wihthout Link
- 16
Hong DS, Sebti SM, Newman RA. et al .
Phase I Trial of a Combination of the Multikinase Inhibitor Sorafenib and the Farnesyltransferase
Inhibitor Tipifarnib in Advanced Malignancies.
Clin Cancer Res.
2009;
Reference Ris Wihthout Link
- 17 Hooper, C. Insulin signaling pathways. htpp://www.abcam.com/index.html?pageconfig=resource&idref=10602&pid=7 abcam Inc., Cambridge, MA, USA 23-5-2009
Reference Ris Wihthout Link
- 18
Huang J, Manning BD.
The TSC1-TSC2 complex: a molecular switchboard controlling cell growth.
Biochem J.
2008;
412
179-190
Reference Ris Wihthout Link
- 19
Hudes G, Carducci M, Tomczak P. et al .
Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.
N Engl J Med.
2007;
356
2271-2281
Reference Ris Wihthout Link
- 20
Jonasch E, Corn P, Pagliaro LC. et al .
Upfront, randomized, phase 2 trial of sorafenib versus sorafenib and low-dose interferon
alfa in patients with advanced renal cell carcinoma: clinical and biomarker analysis.
Cancer.
2009;
Reference Ris Wihthout Link
- 21
Kasuga M, Karlsson FA, Kahn CR.
Insulin stimulates the phosphorylation of the 95 000-dalton subunit of its own receptor.
Science.
1982;
215
185-187
Reference Ris Wihthout Link
- 22
Kim J, Reber HA, Dry SM. et al .
Unfavourable prognosis associated with K-ras gene mutation in pancreatic cancer surgical
margins.
Gut.
2006;
55
1598-1605
Reference Ris Wihthout Link
- 23
Lancet JE, Gojo I, Gotlib J. et al .
A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly
patients with previously untreated acute myelogenous leukemia.
Blood.
2007;
109
1387-1394
Reference Ris Wihthout Link
- 24
Montagut C, Settleman J.
Targeting the RAF-MEK-ERK pathway in cancer therapy.
Cancer Lett.
2009;
283
125-134
Reference Ris Wihthout Link
- 25
Myers Jr MG, White MF.
The new elements of insulin signaling. Insulin receptor substrate-1 and proteins with
SH2 domains.
Diabetes.
1993;
42
643-650
Reference Ris Wihthout Link
- 26
Neubauer A, Maharry K, Mrozek K. et al .
Patients with acute myeloid leukemia and RAS mutations benefit most from postremission
high-dose cytarabine: a Cancer and Leukemia Group B study.
J Clin Oncol.
2008;
26
4603-4609
Reference Ris Wihthout Link
- 27
Pao W, Wang TY, Riely GJ. et al .
KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib.
PLoS Med.
2005;
2
e17
Reference Ris Wihthout Link
- 28
Pilarski R.
Cowden syndrome: a critical review of the clinical literature.
J Genet Couns.
2009;
18
13-27
Reference Ris Wihthout Link
- 29
Rinehart J, Adjei AA, Lorusso PM. et al .
Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced
non-small-cell lung, breast, colon, and pancreatic cancer.
J Clin Oncol.
2004;
22
4456-4462
Reference Ris Wihthout Link
- 30
Rushworth LK, Hindley AD, O'Neill E. et al .
Regulation and role of Raf-1/B-Raf heterodimerization.
Mol Cell Biol.
2006;
26
2262-2272
Reference Ris Wihthout Link
- 31
Sarbassov DD, Guertin DA, Ali SM. et al .
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex.
Science.
2005;
307
1098-1101
Reference Ris Wihthout Link
- 32
Shaw RJ, Cantley LC.
Ras, PI(3)K and mTOR signalling controls tumour cell growth.
Nature.
2006;
441
424-430
Reference Ris Wihthout Link
- 33
Shepherd PR, Withers DJ, Siddle K.
Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling.
Biochem J.
1998;
333
471-490
Reference Ris Wihthout Link
- 34
Skolnik EY, Batzer A, Li N. et al .
The function of GRB2 in linking the insulin receptor to Ras signaling pathways.
Science.
1993;
260
1953-1955
Reference Ris Wihthout Link
- 35
Stephens L, Anderson K, Stokoe D. et al .
Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent
activation of protein kinase B.
Science.
1998;
279
710-714
Reference Ris Wihthout Link
- 36
Tsai J, Lee JT, Wang W. et al .
Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma
activity.
Proc Natl Acad Sci USA.
2008;
105
3041-3046
Reference Ris Wihthout Link
- 37
Ullrich A, Bell JR, Chen EY. et al .
Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes.
Nature.
1985;
313
756-761
Reference Ris Wihthout Link
- 38
Virkamaki A, Ueki K, Kahn CR.
Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin
resistance.
J Clin Invest.
1999;
103
931-943
Reference Ris Wihthout Link
- 39
Vitale A, Volk ML, Pastorelli D. et al .
Use of sorafenib in patients with hepatocellular carcinoma before liver transplantation:
A cost-benefit analysis while awaiting data on sorafenib safety.
Hepatology.
2009;
Reference Ris Wihthout Link
- 40
Wang X, Jiang X.
Post-translational regulation of PTEN.
Oncogene.
2008;
27
5454-5463
Reference Ris Wihthout Link
- 41
Watson RT, Shigematsu S, Chiang SH. et al .
Lipid raft microdomain compartmentalization of TC10 is required for insulin signaling
and GLUT4 translocation.
J Cell Biol.
2001;
154
829-840
Reference Ris Wihthout Link
- 42
Zhang J, Gao Z, Yin J. et al .
S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response
to TNF-(alpha) signaling through IKK2.
J Biol Chem.
2008;
283
35375-35382
Reference Ris Wihthout Link
- 43
Zhu K, Hamilton AD, Sebti SM.
Farnesyltransferase inhibitors as anticancer agents: current status.
Curr Opin Investig Drugs.
2003;
4
1428-1435
Reference Ris Wihthout Link
Correspondence
Prof. Dr. med. H.-U. Häring
Medizinische Klinik IV
Universitätsklinikum
Tübingen
Otfried-Müller-Str 10
D-72076 Tübingen
Germany
Telefon: +49/7071/2982735
Fax: +49/7071/292784
eMail: hans-ulrich.haering@med.uni-tuebingen.de