RCR5: Differential PTEN expression influences the radio-response of prostate cancer cell lines exposed to high-dose per fraction radiotherapy.
1Centre for Cancer Research and Cell Biology, School of Medicine, Dentistry and Biomedical Science, Queens University Belfast, Belfast, UK,2Northern Ireland Cancer Centre, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, UK
Evidence of an alpha/beta ratio (?/?) as low as 1.5 Gy in prostate cancer patients treated with permanent brachytherapy implants and external beam radiotherapy supports the use of a high dose hypofractionated regimen to enhance the therapeutic ratio. Although prostate cancer is a heterogeneous disease, PTEN is a tumour suppressor gene that has been associated with the initiation, progression, and development of castrate-resistant disease through allelic deletion, promoter methylation and mutation. The impact of PTEN status on radiobiological responses to different fractionation schedules has yet to be fully determined.
We aimed to characterize the in vitro radio-response of human prostate cancer cell lines with variable PTEN expression levels (PC3-G14, DU145 NT01 and sh11.02) to different fractionated and hypofractionated radiation schedules. Western blot analysis indicated robust induction of PTEN expression in a Tetracycline-inducible PC3-G14 cell line, whilst significant knockdown of PTEN was achieved using PTEN targeted shRNA in DU145 cells
. ?/? ratios were derived using the Linear Quadratic Model to clonogenic survival data for these cell lines (PC3-G14 PTEN 12.6 Gy, +PTEN 9.5; DU145 NT01 6.3, sh11.02 4.5). No significant differences between the PC3-G14 +/-PTEN cells exposed to 4x 2 Gy fractions were obsereved, however, delivery of the same total dose (8 Gy) in increasing fraction size (either 2 x 4Gy or 1 x 8 Gy) decreased the survival of PTEN cells to a greater extent than +PTEN cells (1.25- and 2-fold decrease, respectively). Conversely, in the DU145 cell models, cells expressing PTEN had higher survival at the higher fractions than the PTEN knockdown cells (2-fold increase).
Differential PTEN status impacts on the survival of cells exposed to fractionated and hypofractionated regimens. In vitro data has in has indicated promising outcomes for the use of high dose hypofractionated radiotherapy in the treatment of prostate cancer. Increasing the dose per fraction using this approach increases the cell killing effect, while increasing the time interval between fractions leads to increased cell survival. The ?/? ratio of in vitro models appears higher than in clinical prostate cancer, however the impact of PTEN status appears to follow radiobiological principles with regard to increases in dose size.