Activation of Sterile20-like kinase 1 in proteasome inhibitor bortezomib-induced apoptosis in oncogenic K-ras-transformed cells

Fuminori Teraishi, Wei Guo, Lidong Zhang, Fengqing Dong, John J. Davis, Takehiko Sasazuki, Senji Shirasawa, Jinsong Liu, Bingliang Fang

Research output: Contribution to journalArticle

16 Citations (Scopus)

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-rastransformed cells with bortezomib resulted in translocation of MSTl 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-rastransformed cells.

Original languageEnglish
Pages (from-to)6072-6079
Number of pages8
JournalCancer Research
Volume66
Issue number12
DOIs
Publication statusPublished - Jun 15 2006

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Proteasome Inhibitors
Phosphotransferases
Apoptosis
Histones
Bortezomib
Neoplasms
Nuclear Export Signals
Caspases
Caspase 3
Small Interfering RNA
Cell Cycle
Cytoplasm
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology

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Activation of Sterile20-like kinase 1 in proteasome inhibitor bortezomib-induced apoptosis in oncogenic K-ras-transformed cells. / Teraishi, Fuminori; Guo, Wei; Zhang, Lidong; Dong, Fengqing; Davis, John J.; Sasazuki, Takehiko; Shirasawa, Senji; Liu, Jinsong; Fang, Bingliang.

In: Cancer Research, Vol. 66, No. 12, 15.06.2006, p. 6072-6079.

Research output: Contribution to journalArticle

Teraishi, F, Guo, W, Zhang, L, Dong, F, Davis, JJ, Sasazuki, T, Shirasawa, S, Liu, J & Fang, B 2006, 'Activation of Sterile20-like kinase 1 in proteasome inhibitor bortezomib-induced apoptosis in oncogenic K-ras-transformed cells', Cancer Research, vol. 66, no. 12, pp. 6072-6079. https://doi.org/10.1158/0008-5472.CAN-06-0125
Teraishi, Fuminori ; Guo, Wei ; Zhang, Lidong ; Dong, Fengqing ; Davis, John J. ; Sasazuki, Takehiko ; Shirasawa, Senji ; Liu, Jinsong ; Fang, Bingliang. / Activation of Sterile20-like kinase 1 in proteasome inhibitor bortezomib-induced apoptosis in oncogenic K-ras-transformed cells. In: Cancer Research. 2006 ; Vol. 66, No. 12. pp. 6072-6079.
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