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: Dan Qu, Xiao-Man Xu, Meng Zhang, Ting-Shu Jiang, Yi Zhang, Sheng-Qi Li
• Journal: Molecular medicine reports (Mol Med Rep) Vol. 12 Issue 1 Pg. 1305-13 (Jul 2015) ISSN: 1791-3004 [Electronic] Greece
• PMID: 25815461 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Phytogenic
• BCL2 protein, human
• Chromones
• Morpholines
• Naphthoquinones
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Tumor Suppressor Protein p53
• bcl-2-Associated X Protein
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• shikonin
• Proto-Oncogene Proteins c-cbl
• Proto-Oncogene Proteins c-akt

Topics

• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects, genetics)
• Cell Line, Tumor
• Chromones (pharmacology)
• Drug Synergism
• Epithelial Cells (drug effects, metabolism, pathology)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Gene Expression Regulation, Neoplastic
• Humans
• Morpholines (pharmacology)
• Naphthoquinones (pharmacology)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Proto-Oncogene Proteins c-cbl (genetics, metabolism)
• Respiratory Mucosa (drug effects, metabolism, pathology)
• Signal Transduction
• Tumor Suppressor Protein p53 (genetics, metabolism)
• bcl-2-Associated X Protein (genetics, metabolism)