title: Association of Sp1 and survivin in epithelial ovarian cancer: Sp1 inhibitor and cisplatin, a novel combination for inhibiting epithelial ovarian cancer cell proliferation.
abstract: The expression of specificity protein 1 (Sp1) and survivin was evaluated in clinical specimens of epithelial ovarian cancer (EOC) patients. When compared to normal tissue, EOC samples showed high expression of Sp1 and survivin using qPCR (Sp1: ∼2-fold; survivin: ∼5-fold) and Western blot (Sp1: >2.6-fold; survivin: >100-fold). The Sp1 inhibitor, and anti-cancer small molecule, tolfenamic acid (TA), was tested to enhance the response of Cisplatin (Cis) in EOC cell lines. Cell viability (CellTiter-Glo), combination index (CalcuSyn software), apoptosis (Annexin-V staining), cell cycle analyses (flow cytometry), and reactive oxygen species (flow cytometry) were determined. Cell migration and invasion was assessed using matrigel coated transwell chambers. Agilent Technologies proteomics analysis identified potential signaling pathways involved. The combination of TA (50 μM) and Cis (5 μM) synergistically increased the growth inhibition in ES2 (∼80 %, p < 0.001) and OVCAR-3 (60 %, p < 0.001) cells. TA or TA + Cis treatment in ES2 cells caused cell cycle arrest in G1 Phase (TA) or S-Phase (TA + Cis) and unregulated reactive oxygen species. Invasion and migration was decreased in ES2 cells. Global proteomic profiling showed modulation of proteins associated with oxidative phosphorylation, apoptosis, electron transport chain, DNA damage, and cell cycle proteins. These results demonstrate an association of Sp1 and survivin in EOC and confirm targeting these candidates with TA potentially sensitizes EOC cells to cisplatin.
authors: Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA.
authors: Umesh T
authors: UT
authors: Sankpal
authors: Department of Gynecologic Oncology, Florida Hospital Cancer Institute, Orlando, FL, 32804, USA.
authors: Susan B
authors: SB
authors: Ingersoll
authors: Department of Gynecologic Oncology, Florida Hospital Cancer Institute, Orlando, FL, 32804, USA.
authors: Sarfraz
authors: S
authors: Ahmad
authors: Department of Gynecologic Oncology, Florida Hospital Cancer Institute, Orlando, FL, 32804, USA.
authors: Robert W
authors: RW
authors: Holloway
authors: Agilent Technologies, Inc., Wilmington, DE, 19808, USA.
authors: Vadiraja B
authors: VB
authors: Bhat
authors: Pre-clinical Services, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA.|Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA.
authors: Jerry W
authors: JW
authors: Simecka
authors: MD Anderson Cancer Center Orlando, Orlando, FL, 32806, USA.
authors: Liz
authors: L
authors: Daniel
authors: Department of Biotechnology, Sambalpur University, Jyoti Vihar, Sambalpur, Odisha, 768019, India.
authors: Ekamber
authors: E
authors: Kariali
authors: Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA.|Molecular and Medical Genetics, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA.
authors: Jamboor K
authors: JK
authors: Vishwanatha
authors: Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA. riyaz.basha@unthsc.edu.|Pre-clinical Services, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA. riyaz.basha@unthsc.edu.|Molecular and Medical Genetics, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA. riyaz.basha@unthsc.edu.
authors: Riyaz
authors: R
authors: Basha
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D000077216:Carcinoma, Ovarian Epithelial; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D040901:Proteomics / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077022:Survivin; D014407:Tumor Cells, Cultured; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D000077022:Survivin; D062367:ortho-Aminobenzoates; C009500:tolfenamic acid; D002945:Cisplatin
keywords: Cisplatin; Epithelial ovarian cancer; Sp1; Survivin; Tolfenamic acid