Suppression of PI3K/Akt signaling by synthetic bichalcone analog TSWU-CD4 induces ER stress- and Bax/Bak-mediated apoptosis of cancer cells
| Autor: | Tian Shung Wu, Ren Yu Huang, Shih-Shun Chen, Mopuru Vijaya Bhaskar Reddy, Meng Liang Lin, Yao Cheng Lu, Yu Ren Liao, Chuan Chun Lee |
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| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Small interfering RNA Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Apoptosis Dantrolene Piperazines Cell Line Phosphatidylinositol 3-Kinases eIF-2 Kinase Chalcones Humans Protein kinase A Endoplasmic Reticulum Chaperone BiP Protein kinase B Caspase 12 Heat-Shock Proteins PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors bcl-2-Associated X Protein Pharmacology Kinase Chemistry Endoplasmic reticulum Biochemistry (medical) Cell Biology Calcium Channel Blockers Endoplasmic Reticulum Stress Mitochondria Cell biology bcl-2 Homologous Antagonist-Killer Protein Biochemistry Unfolded protein response Calcium Protein Multimerization Signal transduction Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Apoptosis. 19:1637-1653 |
| ISSN: | 1573-675X 1360-8185 |
| DOI: | 10.1007/s10495-014-1031-y |
| Popis: | Suppression of the activity of pro-apoptotic Bcl-2-family proteins frequently confers chemoresistance to many human cancer cells. Using subcellular fractionation, the ER calcium (Ca(++)) channel inhibitor dantrolene and small interfering RNA (siRNA) against Bax or Bak, we show that the new synthetic bichalcone analog TSWU-CD4 induces apoptosis in human cancer cells by releasing endoplasmic reticulum (ER)-stored Ca(++) through ER/mitochondrial oligomerization of Bax/Bak. Blockade of the protein kinase RNA-like ER kinase or the unfolded protein response regulator glucose-regulated protein 78 expression by siRNA not only suppressed oligomeric Bax/Bak-mediated pro-caspase-12 cleavage and apoptosis but also resulted in an inhibition of Bcl-2 downregulation induced by TSWU-CD4. Induction of the ER oligomerization of Bax/Bak and apoptosis by TSWU-CD4 were suppressed by Bcl-2 overexpression. Inhibition of lipid raft-associated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling by TSWU-CD4 induced ER stress- and oligomeric Bax/Bak-mediated apoptosis, which were substantially reversed by overexpression of the wt PI3K p85α subunit. Taken together, these results suggest that suppression of lipid raft-associated PI3K/Akt signaling is required for the ER stress-mediated apoptotic activity of Bax/Bak, which is responsible for the ability of TSWU-CD4-treated cancer cells to exit the ER-mitochondrial apoptotic cell death pathway. |
| Databáze: | OpenAIRE |
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