Inhibition of pp2a activity confers a trail-sensitive phenotype during malignant transformation

Hongmei Yang, Xuanyu Chen, Xuegang Wang, Yansheng Li, Shaoyong Chen, Xiaohui Qian, Rong Wang, Li Chen, Weiwei Han, Anming Ruan, Quansheng Du, Aria F. Olumi, Xiaoping Zhang

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

TRAIL is a promising anticancer agent because it induces apoptosis in the majority of human cancer cells but spares the normal cells. To determine the mechanistic nature of how normal cells acquire a TRAIL-sensitive phenotype during the process of malignant transformation, an experimental cell system was developed by sequential introduction of human telomerase reverse transcriptase and SV40 T antigens (large and small) into normal human prostatic epithelial cells (PrEC). This model system demonstrated that inhibition of protein phosphatase 2A (PP2A), either by SV40 small T antigen, okadaic acid, Calyculin A, or PP2A catalytic subunit siRNA, sensitized normal human PrEC and immortalized cells to TRAIL-induced apoptosis. Moreover, sensitization occurred during the premalignant period of tumorigenesis and PP2A exerted its antiapoptotic activity by negatively regulating c-Fos/ AP-1. In addition, low-dose okadaic acid treatment sensitized TRAIL-resistant cancer cells to TRAIL, suggesting that PP2A inhibitors could be used as an enhancer of apoptosis induced by TRAIL or TRAIL-like agents. These data indicate that downregulation of PP2A activity is a critical step for normal cells to acquire a TRAIL-sensitive phenotype during tumorigenesis and that the level of PP2A activity may foretell cellular sensitivity to TRAILinduced apoptosis. Implications: Inhibition of PP2A is a key determinant in acquiring TRAIL sensitivity during tumorigenesis, with c-Fos/AP-1 as an essential mediator. Mol Cancer Res; 12(2); 217-27.

Original languageEnglish (US)
Pages (from-to)217-227
Number of pages11
JournalMolecular Cancer Research
Volume12
Issue number2
DOIs
StatePublished - Feb 1 2014

Fingerprint

Protein Phosphatase 2
Phenotype
Apoptosis
Polyomavirus Transforming Antigens
Okadaic Acid
Carcinogenesis
Transcription Factor AP-1
Period Circadian Proteins
Epithelial Cells
TNF-Related Apoptosis-Inducing Ligand
Neoplasms
Viral Tumor Antigens
Antineoplastic Agents
Small Interfering RNA
Catalytic Domain
Down-Regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Inhibition of pp2a activity confers a trail-sensitive phenotype during malignant transformation. / Yang, Hongmei; Chen, Xuanyu; Wang, Xuegang; Li, Yansheng; Chen, Shaoyong; Qian, Xiaohui; Wang, Rong; Chen, Li; Han, Weiwei; Ruan, Anming; Du, Quansheng; Olumi, Aria F.; Zhang, Xiaoping.

In: Molecular Cancer Research, Vol. 12, No. 2, 01.02.2014, p. 217-227.

Research output: Contribution to journalArticle

Yang, H, Chen, X, Wang, X, Li, Y, Chen, S, Qian, X, Wang, R, Chen, L, Han, W, Ruan, A, Du, Q, Olumi, AF & Zhang, X 2014, 'Inhibition of pp2a activity confers a trail-sensitive phenotype during malignant transformation', Molecular Cancer Research, vol. 12, no. 2, pp. 217-227. https://doi.org/10.1158/1541-7786.MCR-13-0441
Yang, Hongmei ; Chen, Xuanyu ; Wang, Xuegang ; Li, Yansheng ; Chen, Shaoyong ; Qian, Xiaohui ; Wang, Rong ; Chen, Li ; Han, Weiwei ; Ruan, Anming ; Du, Quansheng ; Olumi, Aria F. ; Zhang, Xiaoping. / Inhibition of pp2a activity confers a trail-sensitive phenotype during malignant transformation. In: Molecular Cancer Research. 2014 ; Vol. 12, No. 2. pp. 217-227.
@article{0d62cd55dfe4414fb2273f2a41e39c98,
title = "Inhibition of pp2a activity confers a trail-sensitive phenotype during malignant transformation",
abstract = "TRAIL is a promising anticancer agent because it induces apoptosis in the majority of human cancer cells but spares the normal cells. To determine the mechanistic nature of how normal cells acquire a TRAIL-sensitive phenotype during the process of malignant transformation, an experimental cell system was developed by sequential introduction of human telomerase reverse transcriptase and SV40 T antigens (large and small) into normal human prostatic epithelial cells (PrEC). This model system demonstrated that inhibition of protein phosphatase 2A (PP2A), either by SV40 small T antigen, okadaic acid, Calyculin A, or PP2A catalytic subunit siRNA, sensitized normal human PrEC and immortalized cells to TRAIL-induced apoptosis. Moreover, sensitization occurred during the premalignant period of tumorigenesis and PP2A exerted its antiapoptotic activity by negatively regulating c-Fos/ AP-1. In addition, low-dose okadaic acid treatment sensitized TRAIL-resistant cancer cells to TRAIL, suggesting that PP2A inhibitors could be used as an enhancer of apoptosis induced by TRAIL or TRAIL-like agents. These data indicate that downregulation of PP2A activity is a critical step for normal cells to acquire a TRAIL-sensitive phenotype during tumorigenesis and that the level of PP2A activity may foretell cellular sensitivity to TRAILinduced apoptosis. Implications: Inhibition of PP2A is a key determinant in acquiring TRAIL sensitivity during tumorigenesis, with c-Fos/AP-1 as an essential mediator. Mol Cancer Res; 12(2); 217-27.",
author = "Hongmei Yang and Xuanyu Chen and Xuegang Wang and Yansheng Li and Shaoyong Chen and Xiaohui Qian and Rong Wang and Li Chen and Weiwei Han and Anming Ruan and Quansheng Du and Olumi, {Aria F.} and Xiaoping Zhang",
year = "2014",
month = "2",
day = "1",
doi = "10.1158/1541-7786.MCR-13-0441",
language = "English (US)",
volume = "12",
pages = "217--227",
journal = "Molecular Cancer Research",
issn = "1541-7786",
publisher = "American Association for Cancer Research Inc.",
number = "2",

}

TY - JOUR

T1 - Inhibition of pp2a activity confers a trail-sensitive phenotype during malignant transformation

AU - Yang, Hongmei

AU - Chen, Xuanyu

AU - Wang, Xuegang

AU - Li, Yansheng

AU - Chen, Shaoyong

AU - Qian, Xiaohui

AU - Wang, Rong

AU - Chen, Li

AU - Han, Weiwei

AU - Ruan, Anming

AU - Du, Quansheng

AU - Olumi, Aria F.

AU - Zhang, Xiaoping

PY - 2014/2/1

Y1 - 2014/2/1

N2 - TRAIL is a promising anticancer agent because it induces apoptosis in the majority of human cancer cells but spares the normal cells. To determine the mechanistic nature of how normal cells acquire a TRAIL-sensitive phenotype during the process of malignant transformation, an experimental cell system was developed by sequential introduction of human telomerase reverse transcriptase and SV40 T antigens (large and small) into normal human prostatic epithelial cells (PrEC). This model system demonstrated that inhibition of protein phosphatase 2A (PP2A), either by SV40 small T antigen, okadaic acid, Calyculin A, or PP2A catalytic subunit siRNA, sensitized normal human PrEC and immortalized cells to TRAIL-induced apoptosis. Moreover, sensitization occurred during the premalignant period of tumorigenesis and PP2A exerted its antiapoptotic activity by negatively regulating c-Fos/ AP-1. In addition, low-dose okadaic acid treatment sensitized TRAIL-resistant cancer cells to TRAIL, suggesting that PP2A inhibitors could be used as an enhancer of apoptosis induced by TRAIL or TRAIL-like agents. These data indicate that downregulation of PP2A activity is a critical step for normal cells to acquire a TRAIL-sensitive phenotype during tumorigenesis and that the level of PP2A activity may foretell cellular sensitivity to TRAILinduced apoptosis. Implications: Inhibition of PP2A is a key determinant in acquiring TRAIL sensitivity during tumorigenesis, with c-Fos/AP-1 as an essential mediator. Mol Cancer Res; 12(2); 217-27.

AB - TRAIL is a promising anticancer agent because it induces apoptosis in the majority of human cancer cells but spares the normal cells. To determine the mechanistic nature of how normal cells acquire a TRAIL-sensitive phenotype during the process of malignant transformation, an experimental cell system was developed by sequential introduction of human telomerase reverse transcriptase and SV40 T antigens (large and small) into normal human prostatic epithelial cells (PrEC). This model system demonstrated that inhibition of protein phosphatase 2A (PP2A), either by SV40 small T antigen, okadaic acid, Calyculin A, or PP2A catalytic subunit siRNA, sensitized normal human PrEC and immortalized cells to TRAIL-induced apoptosis. Moreover, sensitization occurred during the premalignant period of tumorigenesis and PP2A exerted its antiapoptotic activity by negatively regulating c-Fos/ AP-1. In addition, low-dose okadaic acid treatment sensitized TRAIL-resistant cancer cells to TRAIL, suggesting that PP2A inhibitors could be used as an enhancer of apoptosis induced by TRAIL or TRAIL-like agents. These data indicate that downregulation of PP2A activity is a critical step for normal cells to acquire a TRAIL-sensitive phenotype during tumorigenesis and that the level of PP2A activity may foretell cellular sensitivity to TRAILinduced apoptosis. Implications: Inhibition of PP2A is a key determinant in acquiring TRAIL sensitivity during tumorigenesis, with c-Fos/AP-1 as an essential mediator. Mol Cancer Res; 12(2); 217-27.

UR - http://www.scopus.com/inward/record.url?scp=84896707863&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84896707863&partnerID=8YFLogxK

U2 - 10.1158/1541-7786.MCR-13-0441

DO - 10.1158/1541-7786.MCR-13-0441

M3 - Article

C2 - 24296757

AN - SCOPUS:84896707863

VL - 12

SP - 217

EP - 227

JO - Molecular Cancer Research

JF - Molecular Cancer Research

SN - 1541-7786

IS - 2

ER -