Rosser Charles J, Tanaka Motoyoshi, Pisters Louis L, Tanaka Noriyoshi, Levy Lawrence B, Hoover David C, Grossman H Barton, McDonnell Timothy J, Kuban Deborah A, Meyn Raymond E
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Gene Ther. 2004 Apr;11(4):273-9. doi: 10.1038/sj.cgt.7700673.
Bcl-2 is associated with resistance to radiotherapy in prostate cancer. It was recently demonstrated that transduction of LNCaP prostate cells with the PTEN gene resulted in Bcl-2 downregulation. We hypothesized that forced expression of PTEN in prostate cancer cells would sensitize cells to radiation, downregulate Bcl-2 expression, and potentiate the G2M block induced by radiation. Four cell lines - PC-3-Bcl-2 (Bcl-2 overexpression, deleted PTEN), PC-3-Neo (wild-type Bcl-2, deleted PTEN), LNCaP (Bcl-2 overexpression, deleted PTEN), and DU-145 (wild-type Bcl-2 and PTEN) - were transduced with a recombinant adenovirus-5 vector expressing the human wild-type PTEN cDNA under the control of a human cytomegalovirus promoter (Ad-MMAC). After correction for the effect of Ad-MMAC on plating efficiency, Ad-MMAC treatment reduced the surviving fractions after 2 Gy as follows: PC-3-Bcl-2, from 60.5 to 3.6%; PC-3-Neo, no reduction; LNCaP, from 29.6 to 16.3%; and DU-145, from 32.7 to 25.7%. PTEN expression was associated with the downregulation of Bcl-2 expression in PC-3-Bcl-2 and LNCaP cell lines. Ad-MMAC plus radiotherapy potentiated the G2M block seen with radiotherapy alone only in PC-3-Bcl-2 cells. These findings suggest that overexpression of Bcl-2 result in radioresistance and inability of radiation to cause its typical G2M cell-cycle arrest.
Bcl-2与前列腺癌放疗抵抗相关。最近有研究表明，用PTEN基因转导LNCaP前列腺细胞可导致Bcl-2表达下调。我们推测，在前列腺癌细胞中强制表达PTEN会使细胞对辐射敏感，下调Bcl-2表达，并增强辐射诱导的G2M期阻滞。用一种在人巨细胞病毒启动子（Ad-MMAC）控制下表达人野生型PTEN cDNA的重组腺病毒-5载体转导了四种细胞系——PC-3-Bcl-2（Bcl-2过表达，PTEN缺失）、PC-3-Neo（野生型Bcl-2，PTEN缺失）、LNCaP（Bcl-2过表达，PTEN缺失）和DU-145（野生型Bcl-2和PTEN）。在校正Ad-MMAC对铺板效率的影响后，Ad-MMAC处理使2 Gy照射后的存活分数降低如下：PC-3-Bcl-2，从60.5%降至3.6%；PC-3-Neo，无降低；LNCaP，从29.6%降至16.3%；DU-145，从32.7%降至25.7%。在PC-3-Bcl-2和LNCaP细胞系中，PTEN表达与Bcl-2表达下调相关。仅在PC-3-Bcl-2细胞中，Ad-MMAC联合放疗增强了单独放疗时出现的G2M期阻滞。这些发现表明，Bcl-2过表达导致放疗抵抗以及辐射无法引起其典型的G2M细胞周期阻滞。
