Stimulation of MC38 tumor growth by insulin analog X10 involves the serine synthesis pathway.
Recent evidence suggests that type II diabetes is associated with increased risk and/or aggressive behavior of several cancers, including those arising from the colon. Concerns have been raised that endogenous hyperinsulinemia and/or exogenous insulin and insulin analogs might stimulate proliferation of neoplastic cells. However, the mechanisms underlying possible growth-promoting effects of insulin and insulin analogs in cancer cells in vivo, such as changes in gene expression, are incompletely described. We observed that administration of the insulin analog X10 significantly increased tumor growth and proliferation in a murine colon cancer model (MC38 cell allografts). Insulin and X10 altered gene expression in MC38 tumors in a similar fashion, but X10 was more potent in terms of the number of genes influenced and the magnitude of changes in gene expression. Many of the affected genes were annotated to metabolism, nutrient uptake, and protein synthesis. Strikingly, expression of genes encoding enzymes in the serine synthesis pathway, recently shown to be critical for neoplastic proliferation, was increased following treatment with insulin and X10. Using stable isotopic tracers and mass spectrometry, we confirmed that insulin and X10 increased glucose contribution to serine synthesis in MC38 cells. The data demonstrate that the tumor growth-promoting effects of insulin and X10 are associated with changes in expression of genes involved in cellular energy metabolism and reveal previously unrecognized effects of insulin and X10 on serine synthesis.
Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote-Ste.-Catherine, Montreal, Quebec, Canada H3T 1E2. hhvd@novonordisk.com
Henning
H
Hvid
Sarah-Maria
SM
Fendt
Marie-José
MJ
Blouin
Elena
E
Birman
Gregory
G
Voisin
Angela Manegold
AM
Svendsen
Russell
R
Frank
Matthew G
MG
Vander Heiden
Gregory
G
Stephanopoulos
Bo Falck
BF
Hansen
Michael
M
Pollak
D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012694:Serine / Q000096:biosynthesis* / Q000378:metabolism; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D007328:Insulin; D012694:Serine