mda-7 (IL-24) inhibits growth and enhances radiosensitivity of glioma cells in vitro via JNK signaling

被引:101
作者
Yacoub, A
Mitchell, C
Lebedeva, IV
Sarkar, D
Su, ZZ
McKinstry, R
Gopalkrishnan, RV
Grant, S
Fisher, PB
Dent, P
机构
[1] Virginia Commonwealth Univ, Dept Radiat Oncol, Richmond, VA 23298 USA
[2] Virginia Commonwealth Univ, Dept Med, Richmond, VA 23298 USA
[3] Columbia Univ Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA
[4] Columbia Univ Coll Phys & Surg, Dept Neurosurg, New York, NY 10032 USA
[5] Columbia Univ Coll Phys & Surg, Dept Urol, New York, NY 10032 USA
关键词
mda-7; GST-MDA-7; radiation; necrosis; glioma; GBM; PI3K; AKT; MAPK; P38; JNK; survival;
D O I
10.4161/cbt.2.4.422
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Despite therapeutic interventions including surgery, chemotherapy and radiotherapy, glioblastoma multiforme (GBM) has a very poor prognosis and novel therapies are required. MDA-7 (IL-24), when expressed via a recombinant replication defective adenovirus, Ad. mda-7, has profound anti-proliferative and cytotoxic effects in a variety of tumor cells, but not in non-transformed cells. The present studies examined the combined impact of Ad. mda-7 and ionizing radiation on the proliferation and survival of GBM cells. Ad. mda-7 reduced the proliferation of rodent and human glioma cells in MTT assays and in colony formation assays. The anti-proliferative effects of Ad. mda-7 were enhanced by radiation in a greater than additive fashion. In vitro, this cellular change correlated with enhanced cell numbers in G(1) /G(0) and G(2)/M phases of the cell cycle, implying Ad. mda-7 radiosensitizes tumor cells in a cell cycle-independent manner. The radiosensitizing effects were not observed in cultures of non-transformed primary astrocytes. The enhanced reduction in growth correlated with increased necrosis. Ad. mda-7 enhanced p38 and ERK1/2 activity but did not alter JNK or Akt activity. Irradiation of cells expressing MDA-7 suppressed ERK1/2 activity and dramatically enhanced JNK1/2 activity without altering either Akt or p38 activity. Inhibition of JNK1/2, but not p38, signaling abolished the radiosensitizing properties of MDA-7. Inhibition of neither ERK1/2 nor PI3K signaling enhanced the anti-proliferative effects of Ad. mda-7, whereas combined inhibition of both pathways enhanced cell killing, suggesting that ERK and PI3K signaling can be protective against MDA-7 lethality.
引用
收藏
页码:347 / 353
页数:7
相关论文
共 51 条
[1]   The intrinsic radiosensitivity of some human tumor cells throughout their cell cycles [J].
Biade, S ;
Stobbe, CC ;
Chapman, JD .
RADIATION RESEARCH, 1997, 147 (04) :416-421
[2]   p53 accumulation in apoptotic macrophages is an energy demanding process that precedes cytochrome c release in response to nitric oxide [J].
Brockhaus, F ;
Brüne, B .
ONCOGENE, 1999, 18 (47) :6403-6410
[3]  
Cartee L, 2000, INT J ONCOL, V16, P413
[4]   The protein product of the tumor suppressor gene, melanoma differentiation-associated gene 7, exhibits immunostimulatory activity and is designated IL-24 [J].
Caudell, EG ;
Mumm, JB ;
Poindexter, N ;
Ekmekcioglu, S ;
Mhashilkar, AM ;
Yang, XHH ;
Retter, MW ;
Hill, P ;
Chada, S ;
Grimm, EA .
JOURNAL OF IMMUNOLOGY, 2002, 168 (12) :6041-6046
[5]   Reovirus therapy of tumors with activated Ras pathway [J].
Coffey, MC ;
Strong, JE ;
Forsyth, PA ;
Lee, PWK .
SCIENCE, 1998, 282 (5392) :1332-1334
[6]   Combined treatment with the checkpoint abrogator UCN-01 and MEK1/2 inhibitors potently induces apoptosis in drug-sensitive and -resistant myeloma cells through an IL-6-independent mechanism [J].
Dai, Y ;
Landowski, TH ;
Rosen, ST ;
Dent, P ;
Grant, S .
BLOOD, 2002, 100 (09) :3333-3343
[7]   Induction of Apoptosis in Human Leukemia Cells by the CDK1 Inhibitor CGP74514A [J].
Dai, Yun ;
Dent, Paul ;
Grant, Steven .
CELL CYCLE, 2002, 1 (02) :143-152
[8]   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
[9]   Down-regulated melanoma differentiation associated gene (MDA-7) expression in human melanomas [J].
Ekmekcioglu, S ;
Ellerhorst, J ;
Mhashilkar, AM ;
Sahin, AA ;
Read, CM ;
Prieto, VG ;
Chada, S ;
Grimm, EA .
INTERNATIONAL JOURNAL OF CANCER, 2001, 94 (01) :54-59
[10]   The effects of pentoxifylline on the survival of human glioma cells with continuous and intermittent stereotactic radiosurgery irradiation [J].
Eley, KW ;
Benedict, SH ;
Chung, TDK ;
Kavanagh, BD ;
Broaddus, WC ;
Schmidt-Ullrich, RKA ;
Lin, PS .
INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 2002, 54 (02) :542-550