Octreotide and the mTOR inhibitor RAD001 (everolimus) block proliferation and interact with the Akt-mTOR-p70S6K pathway in a neuro-endocrine tumour cell Line.
OBJECTIVE
The mode of action of the somatostatin analog octreotide on neuro-endocrine tumour proliferation is largely unknown. Overexpression of the proto-oncogene Akt/PKB (protein kinase B) has been demonstrated in certain neuro-endocrine tumours: Akt activates downstream proteins including mTOR and p70S6K, which play an important role in cell proliferation. RAD001 (everolimus) is a novel agent that is being trialled in the treatment of neuro-endocrine tumours, and is known to interact with mTOR. We explored the mechanism of action of octreotide, RAD001, and their combination on cell proliferation and kinase activation in a neuro-endocrine tumour cell line (rat insulinoma cell line, INS1).


METHODS
Proliferation assays were used to determine the effects of octreotide, RAD001, and their combination on cell proliferation. Western blotting was used to characterize the expression of phosphorylated Akt, phosphorylated TSC2, phosphorylated mTOR, and phosphorylated 70S6K.


RESULTS
Treatment with octreotide and RAD001 inhibited proliferation and attenuated phosphorylation of all downstream targets of Akt: TSC2, mTOR, and p70S6K.


CONCLUSIONS
In this cell model, octreotide and RAD001 appear to act through a similar pathway and inhibit the Akt-mTOR-p70S6 kinase pathway downstream of Akt. There may be some overlapping effects of the two inhibitors on the mTOR pathway, although it is likely that other additional effects may differentiate the two agents.
Grozinsky-Glasberg
Simona
S
Department of Endocrinology, William Harvey Research Institute, Barts and The London, Queen Mary's School of Medicine and Dentistry, University of London, London, UK.
Franchi
Giulia
G
Teng
Mabel
M
Leontiou
Chrysanthia A
CA
Ribeiro de Oliveira
Antônio
A
Dalino
Paolo
P
Salahuddin
Nabila
N
Korbonits
Márta
M
Grossman
Ashley B
AB
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D018358:Neuroendocrine Tumors / Q000378:metabolism* / Q000473:pathology; D015282:Octreotide / Q000378:metabolism / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured
D000068338:Everolimus; D011494:Protein Kinases; C546845:mTOR protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D015282:Octreotide; D020123:Sirolimus