Silencing of the IGF1R gene enhances sensitivity to DNA-damaging agents in both PTEN wild-type and mutant human prostate cancer.
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.
Rochester
Mark A
MA
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Riedemann
Johann
J
Hellawell
Giles O
GO
Brewster
Simon F
SF
Macaulay
Valentine M
VM
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002470:Cell Survival; D004249:DNA Damage; D015536:Down-Regulation; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D034622:RNA Interference; D011839:Radiation, Ionizing; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis* / Q000235:genetics*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins
D000970:Antineoplastic Agents; D025521:Tumor Suppressor Proteins; D017526:Receptor, IGF Type 1; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human