Potentiation of tumor necrosis factor-alpha-induced tumor cell apoptosis by a small molecule inhibitor for anti-apoptotic protein hPEBP4.
hPEBP4 (human phosphatidylethanolamine-binding protein 4) has been identified to be able to potentiate the resistance of breast, prostate, and ovarian cancers, with the preferential expression of hPEBP4, to tumor necrosis factor-alpha (TNF-alpha) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, suggesting that inhibitors targeting the anti-apoptotic protein hPEBP4 may be useful to increase the sensitivity of hPEBP4-expressing cancer cells to TNF-alpha or TRAIL-induced apoptosis. By structure-based virtual screening and following surface plasmon resonance-based binding assay, seven small compounds were found to potently bind with hPEBP4. The hit compounds were further functionally screened for their ability to inhibit cancer cell growth, and one small compound, IOI-42, was identified to be able to promote TNF-alpha-mediated growth inhibition of MCF-7 breast cancer cells. IOI-42 could potentiate TNF-alpha-induced apoptosis of MCF-7 cells by inhibiting hPEBP4 and could suppress anchorage-independent cell growth of MCF-7 cells. We further demonstrated that IOI-42 could reduce the endogenous association of hPEBP4 with Raf-1/MEK1 and enhance the activation of ERK1/2 and JNK while inhibiting Akt activation. Furthermore, IOI-42 also promoted TRAIL-induced cell apoptosis of prostate cancer cells. Taken together, our data suggest that IOI-42, as the first chemical inhibitor of anti-apoptotic protein hPEBP4, may serve as a potential anti-tumor drug by sensitizing tumor cells to apoptotic inducers.
Qiu
Jianming
J
National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Xiao
Jianfeng
J
Han
Chaofeng
C
Li
Nan
N
Shen
Xu
X
Jiang
Hualiang
H
Cao
Xuetao
X
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008958:Models, Molecular; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D049488:Phosphatidylethanolamine Binding Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage; D055672:Static Electricity; D020349:Surface Plasmon Resonance; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
D000970:Antineoplastic Agents; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha