A combinatorial approach for selectively inducing programmed cell death in human pancreatic cancer cells

被引:146
作者
Su, ZZ
Lebedeva, IV
Gopalkrishnan, RV
Goldstein, NI
Stein, CA
Reed, JC
Dent, P
Fisher, PB
机构
[1] Columbia Univ Coll Phys & Surg, Herbert Irving Comprehens Canc Ctr, Dept Urol, New York, NY 10032 USA
[2] Columbia Univ Coll Phys & Surg, Herbert Irving Comprehens Canc Ctr, Dept Pathol, New York, NY 10032 USA
[3] Columbia Univ Coll Phys & Surg, Herbert Irving Comprehens Canc Ctr, Dept Med, New York, NY 10032 USA
[4] Columbia Univ Coll Phys & Surg, Herbert Irving Comprehens Canc Ctr, Dept Neurosurg, New York, NY 10032 USA
[5] DGI Biotechnol, Edison, NJ 08818 USA
[6] Burnham Inst, La Jolla, CA 92037 USA
[7] Virginia Commonwealth Univ, Med Coll Virginia, Dept Radiat Oncol, Richmond, VA 23298 USA
关键词
D O I
10.1073/pnas.171315198
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Pancreatic cancer is an extremely aggressive neoplasm whose incidence equals its death rate. Despite intensive analysis, the genetic changes that mediate pancreatic cancer development and effective therapies for diminishing the morbidity associated with this disease remain unresolved. Through subtraction hybridization, we have identified a gene associated with induction of irreversible growth arrest, cancer reversion, and terminal differentiation in human melanoma cells, melanoma differentiation associated gene-7 (mda-7). Ectopic expression of mda-7 when using a recombinant adenovirus, Ad.mda-7, results in growth suppression and apoptosis in a broad spectrum of human cancers with diverse genetic defects, without exerting deleterious effects in normal human epithelial or fibroblast cells. Despite the apparently ubiquitous antitumor effects of mda-7, pancreatic carcinoma cells are remarkably refractory to Ad.mda-7 induced growth suppression and apoptosis. In contrast, the combination of Ad.mda-7 with antisense phosphorothioate oligonucleotides, which target the K-ras oncogene (a gene that is mutated in 85 to 95% of pancreatic carcinomas), induces a dramatic suppression in growth and a decrease in cell viability by induction of apoptosis. In mutant K-ras pancreatic carcinoma cells, programmed cell death correlates with expression and an increase, respectively, in MDA-7 and BAX proteins and increases in the ratio of BAX to BCL-2 proteins. Moreover, transfection of mutant K-ras pancreatic carcinoma cells with an antisense K-ras expression vector and infection with Ad.mda-7 inhibits colony formation in vitro and tumorigenesis in vivo in nude mice. These intriguing observations demonstrate that a combinatorial approach, consisting of a cancer-specific apoptosis-inducing gene and an oncogene inactivation strategy, may provide the foundation for developing an effective therapy for pancreatic cancer.
引用
收藏
页码:10332 / 10337
页数:6
相关论文
共 48 条
[1]   Matrix survival signaling:: From fibronectin via focal adhesion kinase to c-Jun NH2-terminal kinase [J].
Almeida, EAC ;
Ilic, D ;
Han, Q ;
Hauck, CR ;
Jin, F ;
Kawakatsu, H ;
Schlaepfer, DD ;
Damsky, CH .
JOURNAL OF CELL BIOLOGY, 2000, 149 (03) :741-754
[2]   MOST HUMAN CARCINOMAS OF THE EXOCRINE PANCREAS CONTAIN MUTANT C-K-RAS GENES [J].
ALMOGUERA, C ;
SHIBATA, D ;
FORRESTER, K ;
MARTIN, J ;
ARNHEIM, N ;
PERUCHO, M .
CELL, 1988, 53 (04) :549-554
[3]  
*AM CANC SOC, 2001, CANC FACTS FIG
[4]  
AOKI K, 1995, CANCER RES, V55, P3810
[5]  
Aoki K, 1997, MOL CARCINOGEN, V20, P251, DOI 10.1002/(SICI)1098-2744(199710)20:2<251::AID-MC12>3.3.CO
[6]  
2-P
[7]  
Blaszkowsky Lawrence, 1998, Frontiers in Bioscience, V3, pE214
[8]   ACTIVATION OF MITOGEN-ACTIVATED PROTEIN-KINASE KINASE BY V-RAF IN NIH 3T3 CELLS AND INVITRO [J].
DENT, P ;
HASER, W ;
HAYSTEAD, TAJ ;
VINCENT, LA ;
ROBERTS, TM ;
STURGILL, TW .
SCIENCE, 1992, 257 (5075) :1404-1407
[9]   The roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway; a potential route to radio- and chemo-sensitization of tumor cells resulting in the induction of apoptosis and loss of clonogenicity [J].
Dent, P ;
Jarvis, WD ;
Birrer, MJ ;
Fisher, PB ;
Schmidt-Ullrich, RK ;
Grant, S .
LEUKEMIA, 1998, 12 (12) :1843-1850
[10]   Radiation-induced release of transforming growth factor α activates the epidermal growth factor receptor and mitogen-activated protein kinase pathway in carcinoma cells, leading to increased proliferation and protection from radiation-induced cell death [J].
Dent, P ;
Reardon, DB ;
Park, JS ;
Bowers, G ;
Logsdon, C ;
Valerie, K ;
Schmidt-Ullrich, R .
MOLECULAR BIOLOGY OF THE CELL, 1999, 10 (08) :2493-2506