Albitar Lina, Carter Mark B, Davies Suzy, Leslie Kimberly K
The Reproductive Molecular Biology Laboratory, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, The University of New Mexico Health Science Center, Albuquerque, NM 87131, USA.
Gynecol Oncol. 2007 Jul;106(1):94-104. doi: 10.1016/j.ygyno.2007.03.006. Epub 2007 May 8.
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).
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.
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.
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.
这些研究证明了I型和II型子宫内膜癌细胞中关键肿瘤抑制因子功能缺失突变或下调如何促进癌变以及导致对表皮生长因子受体（EGFR）抑制剂吉非替尼（ZD1839）产生耐药性。
研究了缺乏肿瘤抑制因子PTEN和RB1或仅缺乏PTEN的细胞模型。恢复PTEN、RB1和p53的表达，并评估其对细胞周期、细胞凋亡和细胞周期调节因子的影响。
在因PTEN和RB1缺失而模拟I型子宫内膜癌的Ishikawa H细胞中，重新表达PTEN和RB1增加了凋亡和G1期，减少了S期和G2-M期，这进一步使细胞对吉非替尼敏感。在因缺失该肿瘤抑制因子而模拟II型肿瘤的Hec50co细胞中表达p53，使细胞停滞在G1-S检查点，并诱导细胞凋亡。然而，这并未提高对吉非替尼的敏感性。探索了负责这些变化的细胞周期调节因子的调控，并确定了一个潜在的新治疗靶点MDM2。
II型Hec50co细胞中p53表达下调与吉非替尼耐药有关。此外，在这些耐药细胞中还出现了抑制p53功能的主要因子MDM2的过表达。吉非替尼仅部分阻断MDM2磷酸化，高MDM2表达可能与耐药性有关。
