Title
Consequences of the loss of p53, RB1, and PTEN: relationship to gefitinib resistance in endometrial cancer
Document Type
Article
Peer Reviewed
1
Publication Date
7-1-2007
Journal/Book/Conference Title
Gynecologic oncology
Volume
106
NLM Title Abbreviation
Gynecol Oncol
DOI
10.1016/j.ygyno.2007.03.006
PubMed ID
17490733
Abstract
OBJECTIVE: These studies demonstrate how loss of function mutations or downregulation of key tumor suppressors missing from type I and type II endometrial cancer cells contributes to carcinogenesis and to resistance to the EGFR inhibitor gefitinib (ZD1839). METHODS: Cell models devoid of tumor suppressors PTEN and RB1 or PTEN were studied. PTEN, RB1 and p53 expression was reinstated, and the effects on cell cycle, apoptosis, and cell cycle regulators were evaluated. RESULTS: In Ishikawa H cells that model type I endometrial cancer in the loss of PTEN and RB1, re-expressing PTEN and RB1 increased the apoptotic and G1 phases and decreased the S and G2-M phases, which further sensitize the cells to gefitinib. Expressing p53 in Hec50co that model type II tumors by loss of this tumor suppressor arrested cells at the G1-S checkpoint, and apoptosis was also induced. Yet this did not improve sensitivity to gefitinib. Modulation of the cell cycle regulators responsible for these changes is explored, and a potential new therapeutic target, MDM2, is identified. CONCLUSION: The downregulation of p53 expression in type II Hec50co cells is linked to gefitinib resistance. In addition, the overexpression of MDM2, the principal factor that inhibits p53 function also occurs in these resistant cells. MDM2 phosphorylation is only partially blocked by gefitinib, and high MDM2 expression may relate to drug resistance.
Keywords
Antineoplastic Agents/pharmacology, Cell Cycle/drug effects/genetics, Cell Cycle Proteins/biosynthesis, Cell Line, Tumor, Drug Resistance, Neoplasm, Endometrial Neoplasms/drug therapy/genetics/metabolism, Female, Genes, Tumor Suppressor, Humans, PTEN Phosphohydrolase/deficiency/genetics, Quinazolines/pharmacology, Retinoblastoma Protein/deficiency/genetics, Transfection, Tumor Suppressor Protein p53/deficiency/genetics
URL
http://ir.uiowa.edu/obgyn_pubs/15