IGF1 induces cell proliferation in human pituitary tumors - functional blockade of IGF1 receptor as a novel therapeutic approach in non-functioning tumors.
Insulin-like growth factor (IGF1) and its receptor display potent proliferative and antiapoptotic activities and are considered key players in malignancy. The objective of the study was to explore the role of IGF1 and its downstream pathways in the proliferation of non-functioning pituitary tumor cells and to develop a targeted therapeutic approach for the treatment of these tumors. Cultures of human non-functioning pituitary adenomas and the non-secreting immortalized rat pituitary tumor cell line MtT/E were incubated with IGF1, IGF1 receptor inhibitor or both, and cell viability, proliferation and signaling were examined. Our results show that IGF1 elevated cell proliferation and enhanced cell cycle progression as well as the expression of cyclins D1 and D3. IGF1 also induced the phosphorylation of ERK, Akt and p70S6K. On the other hand, the selective IGF1R inhibitor NVP-AEW541 abrogated IGF1-induced cell proliferation as well as IGF1 receptor phosphorylation and downstream signaling.
Institute of Endocrinology and Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva 49100, Israel; Sackler School of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel. Electronic address: hadarar@clalit.org.il.
Hadara
H
Rubinfeld
Institute of Endocrinology and Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva 49100, Israel; Sackler School of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel.
Adi
A
Kammer
Institute of Endocrinology and Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva 49100, Israel; Sackler School of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel.
Ortal
O
Cohen
Institute of Endocrinology and Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva 49100, Israel; Sackler School of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel.
Alexander
A
Gorshtein
Sackler School of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel; Department of Neurosurgery, Sheba Medical Center, Tel-Hashomer, Israel.
Zvi R
ZR
Cohen
Sackler School of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel; Department of Neurosurgery, Sheba Medical Center, Tel-Hashomer, Israel.
Moshe
M
Hadani
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Israel.
Haim
H
Werner
Institute of Endocrinology and Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva 49100, Israel; Sackler School of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel.
Ilan
I
Shimon
D000236:Adenoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D056743:Cyclin D3 / Q000378:metabolism; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats
D000970:Antineoplastic Agents; C530104:CCND1 protein, human; C534696:CCND3 protein, human; D056743:Cyclin D3; C583557:IGF1 protein, human; C501177:NVP-AEW541; D011743:Pyrimidines; D011758:Pyrroles; D019938:Cyclin D1; D007334:Insulin-Like Growth Factor I
IGF1; IGF1 receptor; IGF1 receptor inhibitor; Pituitary adenomas