Analysis of signaling pathways related to cell proliferation stimulated by insulin analogs in human mammary epithelial cell lines
Open accessAbstract
Insulin and insulin analogs stimulate proliferation of human mammary epithelial cells. We identified and analyzed the signaling pathways related to cell proliferation induced by regular insulin and by four insulin analogs presently approved for therapeutical use. Benign and malignant mammary cell lines showing different insulin receptor (IR) and IGF-I receptor (IGF-IR) expression patterns were studied. Cell proliferation was studied by crystal violet staining (BrdU-FACS analysis). Activation of insulin and IGF signaling pathways was studied by analysis of the phosphorylation status of IGF-IR and of key signaling proteins of the phosphoinositide 3-kinase (PI3K)/Akt and MAP kinase pathways, by the use of specific PI3K and MAP kinase inhibitors, and by silencing of IR and IGF-IR. Lantus stimulated the growth of MCF7 cells, which show high IGF-IR/IR ratio, significantly at 0.3 nmol/l, while regular insulin (Actrapid and bovine insulin) and other insulin analogs (Novorapid, Humalog, and Levemir) stimulated cell growth at 1.5-15 nmol/l concentrations. No difference between Lantus and the other insulin analogs was observed regarding growth stimulation of MCF10A cells showing low IGF-IR/IR ratio. Growth stimulation of MCF7 cells by Lantus was mainly due to strong activation of the IGF-IR and the MAP kinase pathway. Regular insulin and other insulin analogs tested activated mainly the IR and the PI3K/Akt pathway. We conclude that unlike regular insulin and other insulin analogs, Lantus strongly activates the IGF-IR and the MAP kinase pathway in MCF7 cells and is a strong mitogen for cells characterized by a high-IGF-IR/IR ratio.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Substantial prior research has emphasized differences between human insulin and analog insulins with respect to binding affinity to the IGF-I receptor, including evidence that insulin glargine has much higher affinity and higher mitogenic potency than human insulin or other analogs.
“Substantial prior research has emphasized differences between human insulin and analog insulins with respect to binding affinity to the IGF-I receptor, including evidence that insulin glargine has much higher affinity, and higher mitogenic potency, than human insulin or other analogs (120–122).”
From Diabetes and Cancer (2010) · cites this paper as [120]
Knockdown of the IGF-1 receptor, but not the insulin receptor, abolished proliferation of malignant cell lines in response to insulin glargine.
“The affinity of particular analog insulins for the IGF-I receptor is an important issue, in view of evidence that knockdown of the IGF-1 receptor, but not the insulin receptor, abolished proliferation of malignant cell lines in response to insulin glargine (120).”
From Diabetes and Cancer (2010) · cites this paper as [120]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Simultaneous Inference in General Parametric Models
Hothorn, T., Bretz, F., & Westfall, P. H. (2008) · Biometrical Journal · doi:10.1002/bimj.200810425 · Cited by 13,950 · see citing works
White, M. F., & Kahn, C. R. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)42297-6 · Cited by 1,723 · see citing works
Activation and signaling of the p38 MAP kinase pathway
Zarubin, T., & Han, J. (2005) · Cell Research · doi:10.1038/sj.cr.7290257 · Cited by 1,711 · see citing works
Soule, H. D., Maloney, T., Wolman, S. R., Peterson, W., Brenz, R., McGrath, C. M., Russo, J., Pauley, R. J., Jones, R. F., & Brooks, S. C. (1990) · PubMed · Cited by 1,527 · see citing works
Insulin-like growth factors and neoplasia
Pollak, M., Schernhammer, E. S., & Hankinson, S. E. (2004) · Nature reviews. Cancer · doi:10.1038/nrc1387 · Cited by 1,465 · see citing works
Ritz, C., & Streibig, J. C. (2005) · Journal of Statistical Software · doi:10.18637/jss.v012.i05 · Cited by 1,456 · see citing works
The Role of the IGF System in Cancer Growth and Metastasis: Overview and Recent Insights
Samani, A. A., Yakar, S., LeRoith, D., & Brodt, P. (2007) · Endocrine Reviews · doi:10.1210/er.2006-0001 · Cited by 999 · see citing works
Diabetes mellitus and risk of breast cancer: A meta‐analysis
Larsson, S. C., Mantzoros, C. S., & Wolk, A. (2007) · International Journal of Cancer · doi:10.1002/ijc.22717 · Cited by 875 · see citing works
Kurtzhals, P., Schäffer, L., Sørensen, A., Kristensen, C., Jonassen, I., Schmid, C., & Trüb, T. (2000) · Diabetes · doi:10.2337/diabetes.49.6.999 · Cited by 739 · see citing works
Long-term human breast carcinoma cell lines of metastatic origin: Preliminary characterization
Cailleau, R., Olivé, M., & Cruciger, Q. V. J. (1978) · In Vitro · doi:10.1007/bf02616120 · Cited by 679 · see citing works
Establishment and characterization of a cell line of human breast carcinoma origin
Keydar, I., Chen, L., Karby, S., Weiss, F. R., Delarea, J., Radu, M., Chaitcik, S., & Brenner, H. J. (1979) · European Journal of Cancer (1965) · doi:10.1016/0014-2964(79)90139-7 · Cited by 650 · see citing works
Heise, T., Nosek, L., Rønn, B. B., Endahl, L., Heinemann, L., Kapitza, C., & Draeger, E. (2004) · Diabetes · doi:10.2337/diabetes.53.6.1614 · Cited by 614 · see citing works
Estrogen Receptor in a Human Cell Line (MCF-7) from Breast Carcinoma
Brooks, S., Locke, E. R., & Soule, H. D. (1973) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)43537-0 · Cited by 416 · see citing works
The role of insulin receptors and IGF-I receptors in cancer and other diseases
Frasca, F., Pandini, G., Sciacca, L., PEZZINO, V., Squatrito, S., Belfiore, A., & Vigneri, R. (2008) · Archives of Physiology and Biochemistry · doi:10.1080/13813450801969715 · Cited by 408 · see citing works
Torres‐Arzayus, M. I., de Mora, J. F., Yuan, J., Vázquez, F., Bronson, R. T., Rué, M., Sellers, W. R., & Brown, M. A. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.06.027 · Cited by 377 · see citing works
Engel, L. W., Young, N. A., Tralka, T. S., Lippman, M. E., O’Brien, S. J., & Joyce, M. J. (1978) · PubMed · Cited by 371 · see citing works
Elevated insulin receptor content in human breast cancer
Papa, V, Pezzino, V, Costantino, A., Belfiore, A., Giuffrida, D., Frittitta, L., Vannelli, G. B., Brand, R., Goldfine, I. D., & Vigneri, R. (1990) · Journal of Clinical Investigation · doi:10.1172/jci114868 · Cited by 338 · see citing works
The IGF system and breast cancer.
Sachdev, D., & Yee, D. (2001) · Endocrine Related Cancer · doi:10.1677/erc.0.0080197 · Cited by 315 · see citing works
Characterization of a breast cancer cell line derived from a germ-line BRCA1 mutation carrier.
Tomlinson, G. E., Chen, T. T., Stastny, V., Virmani, A. K., Spillman, M. A., Tonk, V. S., Blum, J. L., Schneider, N. R., Wistuba, I. I., Shay, J. W., et al. (1998) · PubMed · Cited by 292 · see citing works
Dufourny, B., Alblas, J., van Teeffelen, H. A. A. M., et al. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.49.31163 · Cited by 261 · see citing works
Insulin receptor expression and function in human breast cancer cell lines.
Milazzo, G., Giorgino, F., Damante, G., Sung, C., Stampfer, M. R., Vigneri, R., Goldfine, I. D., & Belfiore, A. (1992) · PubMed · Cited by 206 · see citing works
Isolation of Two Human Tumor Epithelial Cell Lines From Solid Breast Carcinomas 2
Lasfargues, E. Y., Coutinho, W. G., & Redfield, E. S. (1978) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/61.4.967 · Cited by 189 · see citing works
Hansen, B. F., Danielsen, G. M., Drejer, K., Sørensen, A. R., Wiberg, F. C., KLEIN, H. H., & Lundemose, A. G. (1996) · Biochemical Journal · doi:10.1042/bj3150271 · Cited by 186 · see citing works
Medunjanin, S., Hermani, A., Servi, B. D., Grisouard, J., Rincke, G., & Mayer, D. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m506758200 · Cited by 140 · see citing works
Self-citationSlieker, L. J., Brooke, G. S., DiMarchi, R. D., Flora, D. B., Green, L. K., Hoffmann, J. A., Long, H. B., Fan, L., Shields, J. E., Sundell, K. L., et al. (1997) · Diabetologia · doi:10.1007/s001250051402 · Cited by 138 · see citing works
Yuan, A., Yu, C., Chen, W., Lin, F., Kuo, S.-H., Luh, K., & Yang, P. (2000) · International Journal of Cancer · doi:10.1002/1097-0215(20001120)89:6 · Cited by 138 · see citing works
Insulin‐Like Growth Factors and Neoplasia
Pollak, M. (2004) · Novartis Foundation symposium · doi:10.1002/0470869976.ch6 · Cited by 131 · see citing works
Ahmad, T., Farnie, G., Bundred, N. J., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m306156200 · Cited by 110 · see citing works
Bähr, M., Kolter, T., Seipke, G., & Eckel, J. (1997) · European Journal of Pharmacology · doi:10.1016/s0014-2999(96)00903-x · Cited by 107 · see citing works
Ciaraldi, T. P., Carter, L., Seipke, G., Mudaliar, S. R. D., & Henry, R. R. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.12.8110 · Cited by 104 · see citing works
Berti, L., Kellerer, M., Bossenmaier, B., Seffer, E., Seipke, G., & Häring, H.-U. (1998) · Hormone and Metabolic Research · doi:10.1055/s-2007-978849 · Cited by 93 · see citing works
Evaluation of the Carcinogenic Potential of Insulin Glargine (LANTUS) in Rats and Mice
Stammberger, I., Bube, A., Durchfeld-Meyer, B., Donaubauer, H. H., & Troschau, G. (2002) · International Journal of Toxicology · doi:10.1080/10915810290096306 · Cited by 90 · see citing works
Insulin-like growth factor-I induces cyclin-D1 expression in MG63 human osteosarcoma cells in vitro.
Furlanetto, R. W., Harwell, S. E., & Frick, K. K. (1994) · Molecular Endocrinology · doi:10.1210/mend.8.4.8052269 · Cited by 81 · see citing works
Insulin and insulin-like growth factor-I signal transduction requires p21ras.
Jhun, B. H., Meinkoth, J. L., Leitner, J. W., Draznin, B., & Olefsky, J. M. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)37517-8 · Cited by 69 · see citing works
Lü, K., & Campisi, J. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.9.3889 · Cited by 65 · see citing works
Heise, T., Bott, S., Rave, K., Dressler, A., Rosskamp, R., & Heinemann, L. (2002) · Diabetic Medicine · doi:10.1046/j.1464-5491.2002.00723.x · Cited by 64 · see citing works
Grisouard, J., Medunjanin, S., Hermani, A., Shukla, A. K., & Mayer, D. (2007) · Molecular Endocrinology · doi:10.1210/me.2007-0129 · Cited by 61 · see citing works
Self-citationEckardt, K., May, C., Koenen, M., & Eckel, J. (2007) · Diabetologia · doi:10.1007/s00125-007-0815-9 · Cited by 57 · see citing works
Liefvendahl, E., & Arnqvist, H. (2008) · Hormone and Metabolic Research · doi:10.1055/s-2008-1062739 · Cited by 53 · see citing works
Staiger, K., Hennige, A. M., Staiger, H., et al. (2007) · Hormone and Metabolic Research · doi:10.1055/s-2007-957352 · Cited by 52 · see citing works
Stein, G. S., van Wijnen, A. J., Stein, J. L., Lian, J. B., Pockwinse, S. M., & McNeil, S. M. (1998) · Journal of Cellular Biochemistry · doi:10.1002/(sici)1097-4644(19980801)70:2 · Cited by 47 · see citing works
Fluctuation of Serum Basal Insulin Levels Following Single and Multiple Dosing of Insulin Glargine
Gerich, J. E., Becker, R. H. A., Zhu, R., & Bolli, G. B. (2006) · Diabetes Technology & Therapeutics · doi:10.1089/dia.2006.8.237 · Cited by 45 · see citing works
Insulin aspart: a novel rapid-acting human insulin analogue
Gammeltoft, S., Hansen, B. F., Dideriksen, L., Lindholm, A., Schäffer, L., Trüb, T., Dayan, A. D., & Kurtzhals, P. (1999) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.8.9.1431 · Cited by 43 · see citing works
Staiger, K., Staiger, H., Schweitzer, M. A., Metzinger, E., Balletshofer, B. M., Häring, H., & Kellerer, M. (2005) · Diabetologia · doi:10.1007/s00125-005-1874-4 · Cited by 39 · see citing works
Defining the Role of Insulin Detemir in Basal Insulin Therapy
Morales, J. (2007) · Drugs · doi:10.2165/00003495-200767170-00007 · Cited by 36 · see citing works
Shymko, R. M., Dumont, E., MEYTS, P. D., et al. (1999) · Biochemical Journal · doi:10.1042/bj3390675 · Cited by 34 · see citing works
Extended lifespan and immortalization of human fibroblasts induced by x-ray irradiation
Tsutsui, T., Tanaka, Y., Matsudo, Y., Hasegawa, K., Fujino, T., Kodama, S., & Barrett, J. C. (1997) · Molecular Carcinogenesis · doi:10.1002/(sici)1098-2744(199701)18:1 · Cited by 31 · see citing works
Insulin-like growth factor-I induces cyclin-D1 expression in MG63 human osteosarcoma cells in vitro
Furlanetto, R. W. (1994) · Molecular Endocrinology · doi:10.1210/me.8.4.510 · Cited by 31 · see citing works
Fluctuation and reproducibility of exposure and effect of insulin glargine in healthy subjects*
Becker, R. H. A., Frick, A. D., Teichert, L., Nosek, L., Heinemann, L., Heise, T., & Rave, K. (2008) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2008.00874.x · Cited by 23 · see citing works
Insulin analogues: Action profiles beyond glycaemic control
Eckardt, K., & Eckel, J. (2008) · Archives of Physiology and Biochemistry · doi:10.1080/13813450801983369 · Cited by 16 · see citing works
Shymko, R. M., Dumont, E., MEYTS, P. D., et al. (1999) · Biochemical Journal · doi:10.1042/0264-6021:3390675 · Cited by 14 · see citing works
Shukla, A. K. (2007) · Cited by 2 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 2
- Gliozzo B, Sung CK, Scalia P, Papa V, Frasca F, Sciacca L, Giorgino F, Milazzo G, Goldfine ID, Vigneri R et al. 1998 Insulin-stimulated cell growth in insulin receptor substrate-1-deficient ZR-75-1 cells is mediated by a phosphatidylinositol-3-kinase-independent pathway. Journal of Cellular Biochemistry 70 268-280.
- Schnarr B, Strunz K, Ohsam J, Benner A, Wacker J & Mayer D 2000 Down-regulation of insulin-like growth factor-I receptor and insulin receptor substrate-1 expression in advanced human breast cancer. International Journal of Cancer 89 506-513.
Cited by
Sorted by citations
Giovannucci, E., Harlan, D. M., Archer, M. C., Bergenstal, R. M., Gapstur, S. M., Habel, L. A., Pollak, M., Regensteiner, J. G., & Yee, D. (2010) · Diabetes Care · doi:10.2337/dc10-0666 · Cited by 2,366 · see citing works
The influence of glucose-lowering therapies on cancer risk in type 2 diabetes
Currie, C. J., Poole, C. D., & Gale, E. A. M. (2009) · Diabetologia · doi:10.1007/s00125-009-1440-6 · Cited by 1,124 · see citing works
Vigneri, P., Frasca, F., Sciacca, L., Pandini, G., & Vigneri, R. (2009) · Endocrine Related Cancer · doi:10.1677/erc-09-0087 · Cited by 1,009 · see citing works
He, L., Zhang, S., Zhang, X., Liu, R., Guan, H., & Zhang, H. (2017) · OncoTargets and Therapy · doi:10.2147/ott.s150701 · Cited by 40 · see citing works
Coupling between Nutrient Availability and Thyroid Hormone Activation
Lartey, L. J., Werneck-de-Castro, J. P., O-Sullivan, I., Unterman, T. G., & Bianco, A. C. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.665505 · Cited by 41 · see citing works
- Authors
- Shukla, A., Grisouard, J., Ehemann, V., Hermani, A., Enzmann, H., & Mayer, D.
- Affiliations
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- Federal Institute for Drugs and Medical Devices (DE)
- Corresponding author
- Mayer, Doris
- ORCID
- Shukla, Ashish
- Venue
- Endocrine Related Cancer
- Publisher
- Bioscientifica
- Published
- 2009-06
- Volume
- 16
- Issue
- 2
- Pages
- 429-441
- ISSN
- 1351-0088 (ISSN-L)
- 1479-6821
- OpenAlex
- W2169423532
- Cited by
- 130
- References
- 52
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2022: 1 · 2021: 1 · 2020: 8 · 2019: 4 · 2018: 9 · 2017: 8 · 2016: 7 · 2015: 9 · 2014: 7 · 2013: 8 · 2012: 12
- FWCI
- 14.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrine Related Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bundesinstitut für Arzneimittel und Medizinprodukte
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- insulin analogues, insulin receptor, IGF-1 receptor, mammary epithelial cells, cell proliferation, Lantus, insulin signaling pathway, MAPK signaling, PI3K/Akt signaling, MCF-7 cells, MCF10A cells
- MeSH terms
- Animals, Breast Neoplasms, Cattle, Enzyme Inhibitors, Female, Humans, Insulin, Phosphorylation, Receptor, Insulin, RNA, Messenger, Tumor Cells, Cultured, Immunoblotting, Signal Transduction, Receptor, IGF Type 1, Phosphatidylinositol 3-Kinases, Reverse Transcriptase Polymerase Chain Reaction, MAP Kinase Signaling System, RNA, Small Interfering, Mammary Glands, Human, Cell Proliferation, Proto-Oncogene Proteins c-akt
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
