title: Activation of sterile20-like kinase 1 in proteasome inhibitor bortezomib-induced apoptosis in oncogenic K-ras-transformed cells.
abstract: Bortezomib (PS-341), a specific proteasome inhibitor, exhibits antitumor activity against a wide range of malignancies. However, the molecular mechanisms by which bortezomib causes apoptosis selectively in cancer cells still remain unclear. Ras signaling is involved in multiple cellular processes, including cell cycle progression, differentiation, and apoptosis, and can either promote or inhibit apoptosis depending on the type of apoptotic stimuli and the cell model. Here, we investigated the role of K-ras signaling in bortezomib-induced apoptosis. We found that K-ras-transformed cells were more susceptible to bortezomib-induced apoptosis than were nontransformed cells and that bortezomib-induced apoptosis was mainly caspase dependent in K-ras-transformed cells. We also found that mammalian sterile20-like kinase 1 (MST1) was activated by bortezomib in K-ras-transformed cells and K-ras-mutated cancer cells. Treatment of K-ras-transformed cells with bortezomib resulted in translocation of MST1 from cytoplasm into the nucleus and an increase of phosphorylated histone H2B and histone H2AX. Moreover, pretreatment with leptomycin B, an inhibitor of the nuclear export signal receptor, dramatically enhanced bortezomib-mediated MST1 activation, phosphorylation of histones H2B and H2AX, and apoptosis induction in K-ras-transformed cells. Knockdown of MST1 expression by small interfering RNA diminished bortezomib-induced apoptosis or caspase-3 activation. Our data suggested that bortezomib may be useful for treatment of K-ras-mutated cancer cells, and MST1 is one of the mediators for bortezomib-induced apoptosis in K-ras-transformed cells.
authors.affiliation: Department of Thoracic, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Teraishi
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Lidong
authors.initials: L
authors.lastname: Zhang
authors.forename: Fengqing
authors.initials: F
authors.lastname: Dong
authors.forename: John J
authors.initials: JJ
authors.lastname: Davis
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.forename: Senji
authors.initials: S
authors.lastname: Shirasawa
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.forename: Bingliang
authors.initials: B
authors.lastname: Fang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D011905:Genes, ras; D045325:HCT116 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009154:Mutation; D010766:Phosphorylation; D011480:Protease Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011719:Pyrazines / Q000494:pharmacology*; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D000069286:Bortezomib; D020169:Caspases; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D011480:Protease Inhibitors; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D018631:ras Proteins; C420464:sterile 20-like protein kinase nerve injury-associated kinase; C095566:STK4 protein, human; D000099317:Hippo Kinases