Rochester Mark A, Riedemann Johann, Hellawell Giles O, Brewster Simon F, Macaulay Valentine M
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Cancer Gene Ther. 2005 Jan;12(1):90-100. doi: 10.1038/sj.cgt.7700775.
The type 1 insulin-like growth factor receptor (IGF1R) is overexpressed in prostate cancer, and mediates proliferation, motility, and survival. Many prostate cancers harbor inactivating PTEN mutations, enhancing Akt phosphorylation. This activates the principal antiapoptotic pathway downstream of the IGF1R, calling into question the value of IGF1R targeting in this tumor. The aim of the current study was to assess the effect of IGF1R gene silencing in prostate cancer cells that lack functional PTEN protein. In human DU145, LNCaP and PC3 prostate cancer cells, transfection with IGF1R small interfering RNA induced significant enhancement of apoptosis and inhibition of survival, not only in PTEN wild-type DU145 but also in PTEN mutant LNCaP and PC3. This was attributed to attenuation of IGF signaling via Akt, ERKs and p38. In both DU145 and PC3, IGF1R knockdown led to enhancement of sensitivity to mitoxantrone, etoposide, nitrogen mustard and ionizing radiation. There was no sensitization to paclitaxel or 5-fluorouracil, which do not damage DNA, suggesting that chemosensitization results from impairment of the DNA damage response, in addition to removal of apoptosis protection. These results support the concept of IGF1R targeting in prostate cancer, and indicate that PTEN loss does not render tumor cells refractory to this strategy.
1型胰岛素样生长因子受体（IGF1R）在前列腺癌中过度表达，并介导细胞增殖、运动和存活。许多前列腺癌存在PTEN失活突变，增强了Akt磷酸化。这激活了IGF1R下游主要的抗凋亡途径，使得IGF1R靶向治疗在这种肿瘤中的价值受到质疑。本研究的目的是评估IGF1R基因沉默对缺乏功能性PTEN蛋白的前列腺癌细胞的影响。在人DU145、LNCaP和PC3前列腺癌细胞中，用IGF1R小干扰RNA转染不仅在PTEN野生型DU145细胞中，而且在PTEN突变型LNCaP和PC3细胞中均诱导了凋亡的显著增强和存活的抑制。这归因于通过Akt、细胞外信号调节激酶（ERK）和p38的IGF信号传导减弱。在DU145和PC3细胞中，IGF1R基因敲低均导致对米托蒽醌、依托泊苷、氮芥和电离辐射的敏感性增强。对不损伤DNA的紫杉醇或5-氟尿嘧啶没有增敏作用，这表明除了消除凋亡保护外，化学增敏作用还源于DNA损伤反应的受损。这些结果支持了在前列腺癌中靶向IGF1R的概念，并表明PTEN缺失不会使肿瘤细胞对该策略产生耐药性。
