title: Cbl participates in shikonin-induced apoptosis by negatively regulating phosphoinositide 3-kinase/protein kinase B signaling.
abstract: Shikonin, a naturally occurring naphthoquinone, exhibits anti-tumorigenic activity. However, its precise mechanisms of action have remained elusive. In the present study, the involvement in the action of shikonin of the ubiquitin ligases Cbl-b and c-Cbl, which are negative regulators of phosphoinositide 3-kinase (PI3K) activation, was investigated. Shikonin was observed to reduce cell viability and induce apoptosis and G2/M phase arrest in lung cancer cells. In addition, shikonin increased the protein levels of B-cell lymphoma 2 (Bcl-2)-associated X and p53 and reduced those of Bcl-2. Additionally, shikonin inhibited PI3k/Akt activity and upregulated Cbl protein expression. In addition, a specific inhibitor of PI3K, LY294002, was observed to have a synergistic effect on the proliferation inhibition and apoptotic induction of A549 cells with shikonin. In conclusion, the results of the present study suggested that Cbl proteins promote shikonin-induced apoptosis by negatively regulating PI3K/Akt signaling in lung cancer cells.
authors: Department of Respiratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.
authors: Dan
authors: D
authors: Qu
authors: Department of Respiratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.
authors: Xiao-Man
authors: XM
authors: Xu
authors: Department of Geriatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.
authors: Meng
authors: M
authors: Zhang
authors: Department of Respiratory Medicine, Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, P.R. China.
authors: Ting-Shu
authors: TS
authors: Jiang
authors: Department of Geriatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.
authors: Yi
authors: Y
authors: Zhang
authors: Department of Respiratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.
authors: Sheng-Qi
authors: SQ
authors: Li
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004357:Drug Synergism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009285:Naphthoquinones / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002867:Chromones; D009025:Morpholines; D009285:Naphthoquinones; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D050721:Proto-Oncogene Proteins c-cbl; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C000595707:BCL2 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C016101:shikonin