p14(ARF) modulates the cytolytic effect of ONYX-015 in mesothelioma cells with wild-type p53.
ONYX-015 has been reported to kill selectively tumor cells lacking functional p53. Genetic alterations of INK4a/ARF locus, which is a predominant event in malignant pleural mesothelioma, may result in loss of p14(ARF) and subsequent disruption of p53 pathway in cancer cells. In the present study, ONYX-015 was able to kill three mesothelioma cell lines (H28, H513, and 211H) with wild-type p53 but lacking p14(ARF). In contrast, MS-1 mesothelioma cells, which expressed both p53 and p14(ARF), were resistant to ONYX-015. Introducing p14(ARF) gene into the H28 cell, a mesothelioma cell without p14(ARF) expression, significantly increased the resistance of this cell line to the cytolytic effect of ONYX-015. Our results suggest that human mesotheliomas with wild-type p53 yet lacking p14(ARF) are potential candidates for ONYX-015 therapy.
Yang
C T
CT
Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Taipei, Taiwan.
You
L
L
Uematsu
K
K
Yeh
C C
CC
McCormick
F
F
Jablons
D M
DM
D017501:Adenovirus E1B Proteins / Q000235:genetics; D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D003588:Cytopathogenic Effect, Viral / Q000235:genetics; D016158:Genes, p53; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008654:Mesothelioma / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D010997:Pleural Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000502:physiology*
D017501:Adenovirus E1B Proteins; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D011506:Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53