title: Sestrin-3 modulation is essential for therapeutic efficacy of cucurbitacin B in lung cancer cells.
abstract: Many purified compounds from dietary sources have been investigated for their anticancer activities. The main issue with most agents is their effectiveness at high doses which generally could not be delivered to humans through dietary consumption. Here, we observed that cucurbitacin B, a tetracyclic triterpenoid present in pumpkins, gourds and squashes, exhibits antiproliferative effects on human non-small cell lung cancer (NSCLC) cells at nanomolar concentrations. Treatment with cucurbitacin B (0.2-0.6 μM; 24 h) was found to result in decrease in the viability of EGFR-wild type (A549 and H1792) and EGFR-mutant lung cancer cells (H1650 and H1975) and reduction in cell-colonies but had only minimal effect on normal human bronchial epithelial cells. Treatment with cucurbitacin B also caused inhibition of PI3K/mTOR and signal transducer and activator of transcription (STAT)-3 signaling along with simultaneous activation of AMPKα levels in both EGFR-wild type and EGFR-mutant lung cancer cells. Cucurbitacin B caused specific increase in the protein and mRNA expression of sestrin-3 in EGFR-mutant lung cancer cells, but not in EGFR-wild type cells. Treatment with cucurbitacin B to sestrin-3 siRNA treated EGFR-mutant cells further amplified the decrease in cell-viability and caused more sustained G2-phase cell cycle arrest, suggesting that these effects are mediated partly through sestrin-3. We also found that sestrin-3 has a role in the induction of apoptosis by cucurbitacin B in both EGFR-wild type and EGFR-mutant lung cancer cells. These findings suggest novel mechanism by the modulation of sestrin-3 for the action of cucurbitacin B and suggest that it could be developed as an agent for therapy of NSCLC.
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA and.
authors.forename: Naghma
authors.initials: N
authors.lastname: Khan
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA and.
authors.forename: Farah
authors.initials: F
authors.lastname: Jajeh
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA and.
authors.forename: Mohammad Imran
authors.initials: MI
authors.lastname: Khan
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA and.
authors.forename: Eiman
authors.initials: E
authors.lastname: Mukhtar
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA and.|Department of Zoology, Faculty of Science, Mansoura University, Egypt.
authors.forename: Sameh M
authors.initials: SM
authors.lastname: Shabana
authors.affiliation: Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA and.
authors.forename: Hasan
authors.initials: H
authors.lastname: Mukhtar
mesh_terms: D000072283:A549 Cells; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000008:administration & dosage*; D000084622:Sestrins
chemical_list: D066246:ErbB Receptors; D006360:Heat-Shock Proteins; D019869:Phosphatidylinositol 3-Kinases; D014315:Triterpenes; C485523:SESN3 protein, human; D000084622:Sestrins; C041246:cucurbitacin B; C512478:EGFR protein, human