title: Suppression of PI3K/Akt signaling by synthetic bichalcone analog TSWU-CD4 induces ER stress- and Bax/Bak-mediated apoptosis of cancer cells.
abstract: 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.
authors.affiliation: Department of Medical Laboratory Science and Biotechnology, China Medical University, No. 91, Hsueh-Shih Road, Taichung, 40402, Taiwan, mllinsally@yahoo.com.tw.
authors.forename: Meng-Liang
authors.initials: ML
authors.lastname: Lin
authors.forename: Shih-Shun
authors.initials: SS
authors.lastname: Chen
authors.forename: Ren-Yu
authors.initials: RY
authors.lastname: Huang
authors.forename: Yao-Cheng
authors.initials: YC
authors.lastname: Lu
authors.forename: Yu-Ren
authors.initials: YR
authors.lastname: Liao
authors.forename: Mopuru Vijaya Bhaskar
authors.initials: MV
authors.lastname: Reddy
authors.forename: Chuan-Chun
authors.initials: CC
authors.lastname: Lee
authors.forename: Tian-Shung
authors.initials: TS
authors.lastname: Wu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D053454:Caspase 12 / Q000378:metabolism; D002460:Cell Line; D047188:Chalcones / Q000494:pharmacology*; D003620:Dantrolene / Q000494:pharmacology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology*; D055503:Protein Multimerization; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002118:Calcium; D002121:Calcium Channel Blockers; D053454:Caspase 12; D047188:Chalcones; D003620:Dantrolene; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D051057:Proto-Oncogene Proteins c-akt; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D019892:eIF-2 Kinase; C494772:BAK1 protein, human; C494826:BAX protein, human; C000600957:TSWU-CD4 compound