Tumor-suppressive effects of MBP-1 in non-small cell lung cancer cells.
Lung cancer is the leading cause of cancer death among both men and women. Only approximately 15% of people diagnosed with non-small cell lung cancer (NSCLC) survive this disease beyond 5 years. Thus, novel therapeutic strategies are urgently needed to improve the clinical management of this devastating disease. We have previously shown the antiproliferative effect of MBP-1 on several human cancer cells. In this study, we have examined the potential of MBP-1 as a gene therapeutic candidate in regression of non-small cell lung tumor growth. We have observed that exogenous expression of MBP-1 in NSCLC cells (H1299) induces massive cell death. To determine the gene therapeutic potential of MBP-1, replication-deficient recombinant adenovirus expressing MBP-1 was given intratumorally in human lung cancer xenografts in nude mice. Our results showed a significant regression of lung tumor growth and prolonged survival on treatment with MBP-1 compared with the control groups (saline or dl312). Subsequently, the mechanism of MBP-1-mediated H1299 cell death was investigated. Our results suggested that MBP-1 induced poly(ADP-ribose) polymerase cleavage in H1299 cells; however, treatment with pan-caspase inhibitor did not protect against MBP-1-induced cell death. Cells transduced with MBP-1 displayed early plasma membrane permeability, mitochondrial damage without cytochrome c release, and extensive cytoplasmic vacuolation, yielding a morphotype that is typical of necrosis. Taken together, this study suggests that MBP-1 expression induces a novel form of necrosis-like cell death and MBP-1 could be a potential gene therapeutic candidate against non-small cell lung tumor growth.
Ghosh
Asish K
AK
Department of Pathology and Cancer Center, Saint Louis University, St. Louis, Missouri 63104, USA.
Steele
Robert
R
Ryerse
Jan
J
Ray
Ratna B
RB
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000628:therapy*; D016923:Cell Death; D002455:Cell Division; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000628:therapy*; D026901:Membrane Transport Proteins / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009336:Necrosis; D014157:Transcription Factors / Q000235:genetics*; D014183:Transplantation, Heterologous; D002583:Uterine Cervical Neoplasms / Q000235:genetics
C088830:DENND4A protein, human; D004268:DNA-Binding Proteins; D026901:Membrane Transport Proteins; C120759:TRAPPC2 protein, human; D014157:Transcription Factors