Proteomic profiling drug-induced apoptosis in non-small cell lung carcinoma: identification of RS/DJ-1 and RhoGDIalpha.
The growing knowledge of the tight connection between apoptosis and cancer has lead to an explosion of research revolving around apoptotic induction with chemotherapeutic agents and small molecule inhibitors. The chemotherapeutic agent paclitaxel (Taxol) activates mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase and, combined with MEK inhibition, synergistically enhances apoptosis. Here we implement a proteomic approach using two-dimensional gels coupled with mass spectrometry to identify proteins altered with this coordinated combination treatment. We found that the combined treatment of paclitaxel and MEK inhibitor uniquely altered the proteins RS/DJ-1 (RNA-binding regulatory subunit/DJ-1 PARK7) and RhoGDIalpha (Rho GDP-dissociation inhibitor alpha). Functional proteomic analysis by exogenous expression or short interfering RNA targeting confirmed a role in survival and apoptosis for these proteins. Analysis of primary lung tumors with matched adjacent normal tissue confirmed RS/DJ-1 overexpression in non-small cell lung carcinoma. This study shows the power of proteomic profiling coupled with functional analysis for the discovery of novel molecular targets and potential cancer cell-specific biomarkers.
Lineberger Comprehensive Cancer Center, Departments of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Jeffrey P
JP
MacKeigan
Casey M
CM
Clements
John D
JD
Lich
R Marshall
RM
Pope
Yaacov
Y
Hod
Jenny P-Y
JP
Ting
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002070:Butadienes / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D048728:MAP Kinase Kinase Kinase 1; D009570:Nitriles / Q000008:administration & dosage; D015513:Oncogene Proteins / Q000378:metabolism*; D017239:Paclitaxel / Q000008:administration & dosage; D000071617:Protein Deglycase DJ-1; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D040901:Proteomics / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors
D002070:Butadienes; D004791:Enzyme Inhibitors; D020730:Guanine Nucleotide Dissociation Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009570:Nitriles; D015513:Oncogene Proteins; C113580:U 0126; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1; D017239:Paclitaxel