Microtubule-damaging agents enhance RASSFlA-induced cell death in lung cancer cell lines

Young M. Whang, Kyong Hwa Park, Hae Y. Jung, Uk Hyun Jo, Yeul Hong Kim

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

BACKGROUND: Tumor suppressor gene product RASSF1A has been reported to induce mitotic arrest and apoptosis through its interaction with microtubule and binding to the Ras effector NORE1. Despite this promising antitumor action of microtubule-targeted drugs, clinical studies demonstrated that paclitaxel (TXL) and vincristine (VCS) have differential antitumor effects, depending on the status of microtubule- related genes in lung cancer patients. In this study, to provide effective chemotherapeutic treatment for lung cancer patients with the microtubule-targeted drugs, the authors investigated whether RASSF1A could enhance sensitivity to TXL and VCS, as an intrinsic microtubule modulator, in nonsmall cell lung cancer (NSCLC) cells. METHODS: The growth inhibitory effects of TXL and VCS on RASSF7A-transfected cells were assessed using clonogenic and flow cytometry-based propidium iodide-labeled assay. The levels of mitosis-related proteins in RASSF7A-transfected cells after treatment with TXL or VCS were examined by Western blot analysis and in vitro kinase assay. RESULTS: RASSF1A enhanced the growth inhibitory effect of TXL and VCS on NSCLC cells and bronchial epithelial transformed cells (BEAS-2B) by inducing cell cycle arrest at the G2/M-phase. Accumulation of cyclin B1, G 2/M-phase-related protein, was observed when RASSF7A-transfected H1299 cells were treated with TXL or VCS, accompanied with an increase of cyclin A. Inhibition of the activity of cyclin B1/Cdc2 complex by RASSF1A and TXL or VCS was confirmed by kinase assay and knockdown of RASSF1A expression by using small interfering RNA. CONCLUSIONS: RSAAF1A protein has a cooperative growth inhibitory effect with microtubule-targeted drugs through cyclin B1 accumulation on NSCLC cells, suggesting novel insights for the selection of chemotherapeutic agents.

Original languageEnglish
Pages (from-to)1253-1266
Number of pages14
JournalCancer
Volume115
Issue number6
DOIs
Publication statusPublished - 2009 Mar 15

Fingerprint

Vincristine
Microtubules
Lung Neoplasms
Cell Death
Cell Line
Cyclin B1
Non-Small Cell Lung Carcinoma
Cell Division
Cyclin G
Phosphotransferases
Tubulin Modulators
Growth
Pharmaceutical Preparations
Cyclin A
Proteins
Propidium
G2 Phase
Paclitaxel
Cell Cycle Checkpoints
Tumor Suppressor Genes

Keywords

  • Cyclin A
  • Cyclin B1
  • Lung cancer
  • Paclitaxel
  • RASSF1A
  • Vincristine

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Microtubule-damaging agents enhance RASSFlA-induced cell death in lung cancer cell lines. / Whang, Young M.; Park, Kyong Hwa; Jung, Hae Y.; Jo, Uk Hyun; Kim, Yeul Hong.

In: Cancer, Vol. 115, No. 6, 15.03.2009, p. 1253-1266.

Research output: Contribution to journalArticle

Whang, Young M. ; Park, Kyong Hwa ; Jung, Hae Y. ; Jo, Uk Hyun ; Kim, Yeul Hong. / Microtubule-damaging agents enhance RASSFlA-induced cell death in lung cancer cell lines. In: Cancer. 2009 ; Vol. 115, No. 6. pp. 1253-1266.
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abstract = "BACKGROUND: Tumor suppressor gene product RASSF1A has been reported to induce mitotic arrest and apoptosis through its interaction with microtubule and binding to the Ras effector NORE1. Despite this promising antitumor action of microtubule-targeted drugs, clinical studies demonstrated that paclitaxel (TXL) and vincristine (VCS) have differential antitumor effects, depending on the status of microtubule- related genes in lung cancer patients. In this study, to provide effective chemotherapeutic treatment for lung cancer patients with the microtubule-targeted drugs, the authors investigated whether RASSF1A could enhance sensitivity to TXL and VCS, as an intrinsic microtubule modulator, in nonsmall cell lung cancer (NSCLC) cells. METHODS: The growth inhibitory effects of TXL and VCS on RASSF7A-transfected cells were assessed using clonogenic and flow cytometry-based propidium iodide-labeled assay. The levels of mitosis-related proteins in RASSF7A-transfected cells after treatment with TXL or VCS were examined by Western blot analysis and in vitro kinase assay. RESULTS: RASSF1A enhanced the growth inhibitory effect of TXL and VCS on NSCLC cells and bronchial epithelial transformed cells (BEAS-2B) by inducing cell cycle arrest at the G2/M-phase. Accumulation of cyclin B1, G 2/M-phase-related protein, was observed when RASSF7A-transfected H1299 cells were treated with TXL or VCS, accompanied with an increase of cyclin A. Inhibition of the activity of cyclin B1/Cdc2 complex by RASSF1A and TXL or VCS was confirmed by kinase assay and knockdown of RASSF1A expression by using small interfering RNA. CONCLUSIONS: RSAAF1A protein has a cooperative growth inhibitory effect with microtubule-targeted drugs through cyclin B1 accumulation on NSCLC cells, suggesting novel insights for the selection of chemotherapeutic agents.",
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AU - Whang, Young M.

AU - Park, Kyong Hwa

AU - Jung, Hae Y.

AU - Jo, Uk Hyun

AU - Kim, Yeul Hong

PY - 2009/3/15

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N2 - BACKGROUND: Tumor suppressor gene product RASSF1A has been reported to induce mitotic arrest and apoptosis through its interaction with microtubule and binding to the Ras effector NORE1. Despite this promising antitumor action of microtubule-targeted drugs, clinical studies demonstrated that paclitaxel (TXL) and vincristine (VCS) have differential antitumor effects, depending on the status of microtubule- related genes in lung cancer patients. In this study, to provide effective chemotherapeutic treatment for lung cancer patients with the microtubule-targeted drugs, the authors investigated whether RASSF1A could enhance sensitivity to TXL and VCS, as an intrinsic microtubule modulator, in nonsmall cell lung cancer (NSCLC) cells. METHODS: The growth inhibitory effects of TXL and VCS on RASSF7A-transfected cells were assessed using clonogenic and flow cytometry-based propidium iodide-labeled assay. The levels of mitosis-related proteins in RASSF7A-transfected cells after treatment with TXL or VCS were examined by Western blot analysis and in vitro kinase assay. RESULTS: RASSF1A enhanced the growth inhibitory effect of TXL and VCS on NSCLC cells and bronchial epithelial transformed cells (BEAS-2B) by inducing cell cycle arrest at the G2/M-phase. Accumulation of cyclin B1, G 2/M-phase-related protein, was observed when RASSF7A-transfected H1299 cells were treated with TXL or VCS, accompanied with an increase of cyclin A. Inhibition of the activity of cyclin B1/Cdc2 complex by RASSF1A and TXL or VCS was confirmed by kinase assay and knockdown of RASSF1A expression by using small interfering RNA. CONCLUSIONS: RSAAF1A protein has a cooperative growth inhibitory effect with microtubule-targeted drugs through cyclin B1 accumulation on NSCLC cells, suggesting novel insights for the selection of chemotherapeutic agents.

AB - BACKGROUND: Tumor suppressor gene product RASSF1A has been reported to induce mitotic arrest and apoptosis through its interaction with microtubule and binding to the Ras effector NORE1. Despite this promising antitumor action of microtubule-targeted drugs, clinical studies demonstrated that paclitaxel (TXL) and vincristine (VCS) have differential antitumor effects, depending on the status of microtubule- related genes in lung cancer patients. In this study, to provide effective chemotherapeutic treatment for lung cancer patients with the microtubule-targeted drugs, the authors investigated whether RASSF1A could enhance sensitivity to TXL and VCS, as an intrinsic microtubule modulator, in nonsmall cell lung cancer (NSCLC) cells. METHODS: The growth inhibitory effects of TXL and VCS on RASSF7A-transfected cells were assessed using clonogenic and flow cytometry-based propidium iodide-labeled assay. The levels of mitosis-related proteins in RASSF7A-transfected cells after treatment with TXL or VCS were examined by Western blot analysis and in vitro kinase assay. RESULTS: RASSF1A enhanced the growth inhibitory effect of TXL and VCS on NSCLC cells and bronchial epithelial transformed cells (BEAS-2B) by inducing cell cycle arrest at the G2/M-phase. Accumulation of cyclin B1, G 2/M-phase-related protein, was observed when RASSF7A-transfected H1299 cells were treated with TXL or VCS, accompanied with an increase of cyclin A. Inhibition of the activity of cyclin B1/Cdc2 complex by RASSF1A and TXL or VCS was confirmed by kinase assay and knockdown of RASSF1A expression by using small interfering RNA. CONCLUSIONS: RSAAF1A protein has a cooperative growth inhibitory effect with microtubule-targeted drugs through cyclin B1 accumulation on NSCLC cells, suggesting novel insights for the selection of chemotherapeutic agents.

KW - Cyclin A

KW - Cyclin B1

KW - Lung cancer

KW - Paclitaxel

KW - RASSF1A

KW - Vincristine

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