New Modes of GPCR Signalling

Inhibition of Protein Phosphatase 2A Activity Plays a Key Role for Normal
Human Cells to Acquire TRAIL-Sensitive Phenotype during Tumorigenesis
Yansheng Li1, Yajun Xiao1, Xuegang Wang1, Shaoyong Chen2, Siping Zeng1, Changshuai
Shao1, Xiaohui Qian1,Rong Wang1, Xuanyu Chen1, Quansheng Du3, Aria F. Olumi4,
Hongmei Yang5, Xiaoping Zhang1§
1. Department of Urology, Union Hospital, Tongji Medical School, Huazhong University of
Science and Technology, Wuhan 430022, China, 2.Cancer Biology Program,
Hematology-Oncology Division, Department of Medicine, Beth Israel Deaconess Medical
Center, Harvard Medical School, Boston, Massachusetts 02215, USA 3.Cancer Center,
Medical College of Georgia, Augusta, GA 30912, USA4. Department of Urology,
Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
5.Department of Pathogen Biology, Tongji Medical School, Huazhong University of Science
and Technology, Wuhan 430030, China
Aim: Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a promising
anticancer agent because it induces apoptosis in most cancer cells but spares normal cells. The
aim of the study is to determine how normal human cells acquire TRAIL-sensitive phenotype
during the process of malignant transformation. Methods: An experimental cell system was
developed by sequential introduction of hTERT, SV40 LT, SV40 ST and H-Ras into normal
human prostatic epithelial cells. Then these cells were treated with TRAIL by using MTT assay.
After determining which cells became sensitive to TRAIL, the underlying mechanisms were
explored. Results: For the first time, we demonstrate that introduction of SV40 ST into cells
changes TRAIL phenotype from TRAIL-resistant to TRAIL-sensitive, activity inhibition of the
protein phosphatase 2A (PP2A) either by SV40 ST or okadaic acid (OA) sensitizes normal
human prostatic epithelial cells to TRAIL-induced apoptosis during premalignant period of
tumorigenesis and tumor suppressor gene PP2A may exert its antiapoptotic by negatively
regulating c-Fos/AP-1. In addition, low-dose OA treatment sensitizes TRAIL-resistant cancer
cells to TRAIL, which indicates PP2A inhibitors such as OA can potentially used as an
enhancer of apoptosis induced by TRAIL or TRAIL-like agents. Conclusion: Inhibition of
PP2A activity is a key step for normal human cells to acquire TRAIL-sensitive phenotype
during tumorigenesis, and lower PP2A activity might be a major determinant for cancer cells to
be sensitive to TRAIL-induced apoptosis.
Key Words: TRAIL, the protein phosphatase 2A (PP2A), Apoptosis, SV40 ST, Okadaic acid
(OA)
Grant Support: the National Natural Science Foundation of China (NSFC) (30572139),
(30872924) and Program for New Century Excellent Talents in University from Department of
Education of China (NCET-08-0223) to XZ
§ Corresponding Authors:
Xiaoping Zhang:1277 Jiefang Dadao,Wuhan 430022,Hubei Province,China, Department of
Urology, Union Hospital, Email: xiaoping.zhang2008@gmail.com