Syrbactin class proteasome inhibitor-induced apoptosis and autophagy occurs in association with p53 accumulation and Akt/PKB activation in neuroblastoma.
Syrbactins belong to a new class of proteasome inhibitors which include syringolins and glidobactins. These small molecules are structurally distinct from other, well-established proteasome inhibitors, and bind the eukaryotic 20S proteasome by a novel mechanism. In this study, we examined the effects of syringolin A (SylA) and glidobactin A (GlbA) as well as two synthetic SylA-analogs (SylA-PEG and SylA-LIP) in human neuroblastoma (SK-N-SH), human multiple myeloma (MM1.S, MM1.RL, and U266), and human ovarian cancer (SKOV-3) cells. While all four syrbactins inhibited cell proliferation in a dose-dependent manner, GlbA was most potent in both dexamethasone-sensitive MM1.S cells (IC(50): 0.004microM) and dexamethasone-resistant MM1.RL cells (IC(50): 0.005microM). Syrbactins also inhibited the chymotrypsin-like proteasome activity in a dose-dependent fashion, and GlbA was most effective in SK-N-SH cells (IC(50): 0.015microM). The GlbA-promoted inhibition of proteasomal activity in SK-N-SH cells resulted in the accumulation of ubiquitinated proteins and tumor suppressor protein p53 and led to apoptotic cell death in a time-dependent manner. GlbA treatment also promoted the activation of Akt/PKB via phosphorylation at residue Ser(473) and induced autophagy as judged by the presence of the lipidated form of microtubule-associated protein 1 light chain 3 (LC3) and autophagosomes. Collectively, our data suggest that syrbactins belong to a new and effective proteasome inhibitor class which promotes cell death. Proteasome inhibition is a promising strategy for targeted anticancer therapy and syrbactins are a new class of inhibitors which provide a structural platform for the development of novel, proteasome inhibitor-based drug therapeutics.
Archer
Crystal R
CR
Cancer Research Center of Hawaii, University of Hawaii at Manoa, Honolulu, 96813, USA.
Koomoa
Dana-Lynn T
DL
Mitsunaga
Erin M
EM
Clerc
Jérôme
J
Shimizu
Mariko
M
Kaiser
Markus
M
Schellenberg
Barbara
B
Dudler
Robert
R
Bachmann
André S
AS
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000970:Antineoplastic Agents; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; D016159:Tumor Suppressor Protein p53; C407267:syringolin A; C057878:glidobactin A; D051057:Proto-Oncogene Proteins c-akt