PAX5 is expressed in small-cell lung cancer and positively regulates c-Met transcription.
PAX5 is a nuclear transcription factor required for B cell development, and its expression was evaluated in upper aerodigestive malignancies and pancreatic cancer by immunoblotting. The PAX5 protein expression was relatively strong in small-cell lung cancer (SCLC, 11/12); however, its expression was not detected in non-SCLC (NSCLC, n=13), mesothelioma (n=7), pancreatic (n=6), esophageal (n=6) and head and neck cancer cell lines (n=12). In comparison, PAX8 and PAX3 expressions were absent or non-detectable in SCLC cell lines; however, PAX8 was expressed in most of the tested NSCLC cell lines (13/13) and also frequently in all the other cell lines. We also detected frequent expressions of PAX2 and PAX9 protein in the various cell lines. Utilizing neuroendocrine tumor samples, we found that the frequency as well as the average intensity of the expression of PAX5 increased from pulmonary carcinoid (9%, moderate and strong PAX5 expression, n=44), to large-cell neuroendocrine carcinoma (LCNC, 27%, n=11) to SCLC (33%, n=76). FISH analysis revealed no translocations of the PAX5 gene, but polyploidy in some SCLC tumor tissues (6/37). We determined that PAX5 could regulate the transcription of c-Met using luciferase-coupled reporter and chromatin immunoprecipitation analysis. In addition, the phospho-c-Met (active form) and PAX5 were both localized to the same intra-nuclear compartment in hepatocyte growth factor treated SCLC cells and interacted with each other. Finally, we determined the therapeutic translational potential of PAX5 using PAX5 knockdown SCLC cells in conjunction with Topoisomerase 1 (SN38) and c-Met (SU11274) inhibitors. Loss of endogenous PAX5 significantly decreased the viability of SCLC cells, especially when combined with SN38 or SU11274, and maximum effect was seen when both inhibitors were used. Therefore, we propose that PAX5 could be an important regulator of c-Met transcription and a potential target for therapy in SCLC.
Kanteti
Rajani
R
Department of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL 60637, USA.
Nallasura
Vidya
V
Loganathan
Sivakumar
S
Tretiakova
Maria
M
Kroll
Todd
T
Krishnaswamy
Soundararajan
S
Faoro
Leonardo
L
Cagle
Philip
P
Husain
Aliya N
AN
Vokes
Everett E
EE
Lang
Deborah
D
Salgia
Ravi
R
D017209:Apoptosis; D018278:Carcinoma, Neuroendocrine / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004252:DNA Mutational Analysis; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D017404:In Situ Hybridization, Fluorescence; D007211:Indoles / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051761:Paired Box Transcription Factors / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000378:metabolism; D059004:Topoisomerase I Inhibitors
C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D007211:Indoles; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D051761:Paired Box Transcription Factors; D010879:Piperazines; D034741:RNA, Small Interfering; D013449:Sulfonamides; D059004:Topoisomerase I Inhibitors; D019859:Proto-Oncogene Proteins c-met; D004264:DNA Topoisomerases, Type I