Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines

Ying Wang, Arun K. Rishi, Vineshkumar T. Puliyappadamba, Sunita Sharma, Huanjie Yang, Adi Tarca, Q. Ping Dou, Fulvio Lonardo, John C. Ruckdeschel, Harvey I. Pass, Anil Wali

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Introduction: Thoracic malignancies and human breast cancer (HBC) continue to be aggressive solid tumors that are poor responders to the existing conventional standard chemotherapeutic approaches. Malignant pleural mesothelioma (MPM) is an asbestos-related tumor of the thoracic pleura that lacks effective treatment options. Altered ubiquitin proteasome pathway is frequently encountered in many malignancies including HBC and MPM and thus serves as an important target for therapeutic intervention strategies. Although proteasome inhibitor Velcade (Bortezomib) has been under clinical investigation for a number of cancers, limited preclinical studies with this agent have thus far been conducted in HBC and MPM malignancies. Purpose: To study the biological and molecular responses of MPM and HBC cells to Velcade treatments, and to identify mechanisms involved in transducing growth inhibitory effects of this agent. Methods: Flow-cytometric analyses coupled with western immunoblotting and gene-array methodologies were utilized to determine mechanisms of Velcade-dependent growth suppression of five MPM (H2595, H2373, H2452, H2461, and H2714) and two breast cancer (MDA MB-468, SKBR-3) cell lines. Results: Our data revealed significant reduction in cell growth properties that were dose and time dependent. Velcade treatment resulted in G2M phase arrest, increased expression of cyclin-dependent kinase inhibitor p21 and pro-apoptotic protein Bax. Pretreatment of mesothelioma cells with Velcade showed synergistic effect with cisplatin combination regimens. High-throughput gene expression profiling among Velcade treated and untreated mesothelioma cell lines resulted in identification of novel transducers of apoptosis such as CARP-1, XAF1, and Troy proteins. Conclusions: Velcade targets cell cycle and apoptosis signaling to suppress MPM and HBC growth in part by activating novel transducers of apoptosis. This pilot study has paved way for further in-depth analysis of the downstream target molecules associated with presensitization of mesothelioma cells in finding effective therapeutic treatment options for both mesothelioma and recalcitrant breast cancers.

Original languageEnglish (US)
Pages (from-to)455-466
Number of pages12
JournalCancer Chemotherapy and Pharmacology
Volume66
Issue number3
DOIs
StatePublished - Aug 1 2010

Fingerprint

Mesothelioma
Proteasome Endopeptidase Complex
Cells
Apoptosis
Breast Neoplasms
Cell Line
Neoplasms
Growth
Transducers
Tumors
Thorax
Cyclin-Dependent Kinase Inhibitor p21
Apoptosis Regulatory Proteins
Proteasome Inhibitors
Bortezomib
Pleura
Asbestos
Cell growth
Gene Expression Profiling
Ubiquitin

Keywords

  • Apoptosis
  • Bortezomib (Velcade)
  • Gene expression
  • Malignant pleural mesothelioma

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines. / Wang, Ying; Rishi, Arun K.; Puliyappadamba, Vineshkumar T.; Sharma, Sunita; Yang, Huanjie; Tarca, Adi; Dou, Q. Ping; Lonardo, Fulvio; Ruckdeschel, John C.; Pass, Harvey I.; Wali, Anil.

In: Cancer Chemotherapy and Pharmacology, Vol. 66, No. 3, 01.08.2010, p. 455-466.

Research output: Contribution to journalArticle

Wang, Y, Rishi, AK, Puliyappadamba, VT, Sharma, S, Yang, H, Tarca, A, Dou, QP, Lonardo, F, Ruckdeschel, JC, Pass, HI & Wali, A 2010, 'Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines', Cancer Chemotherapy and Pharmacology, vol. 66, no. 3, pp. 455-466. https://doi.org/10.1007/s00280-009-1181-8
Wang, Ying ; Rishi, Arun K. ; Puliyappadamba, Vineshkumar T. ; Sharma, Sunita ; Yang, Huanjie ; Tarca, Adi ; Dou, Q. Ping ; Lonardo, Fulvio ; Ruckdeschel, John C. ; Pass, Harvey I. ; Wali, Anil. / Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines. In: Cancer Chemotherapy and Pharmacology. 2010 ; Vol. 66, No. 3. pp. 455-466.
@article{8c8105a2493946328edde7692b01bf8f,
title = "Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines",
abstract = "Introduction: Thoracic malignancies and human breast cancer (HBC) continue to be aggressive solid tumors that are poor responders to the existing conventional standard chemotherapeutic approaches. Malignant pleural mesothelioma (MPM) is an asbestos-related tumor of the thoracic pleura that lacks effective treatment options. Altered ubiquitin proteasome pathway is frequently encountered in many malignancies including HBC and MPM and thus serves as an important target for therapeutic intervention strategies. Although proteasome inhibitor Velcade (Bortezomib) has been under clinical investigation for a number of cancers, limited preclinical studies with this agent have thus far been conducted in HBC and MPM malignancies. Purpose: To study the biological and molecular responses of MPM and HBC cells to Velcade treatments, and to identify mechanisms involved in transducing growth inhibitory effects of this agent. Methods: Flow-cytometric analyses coupled with western immunoblotting and gene-array methodologies were utilized to determine mechanisms of Velcade-dependent growth suppression of five MPM (H2595, H2373, H2452, H2461, and H2714) and two breast cancer (MDA MB-468, SKBR-3) cell lines. Results: Our data revealed significant reduction in cell growth properties that were dose and time dependent. Velcade treatment resulted in G2M phase arrest, increased expression of cyclin-dependent kinase inhibitor p21 and pro-apoptotic protein Bax. Pretreatment of mesothelioma cells with Velcade showed synergistic effect with cisplatin combination regimens. High-throughput gene expression profiling among Velcade treated and untreated mesothelioma cell lines resulted in identification of novel transducers of apoptosis such as CARP-1, XAF1, and Troy proteins. Conclusions: Velcade targets cell cycle and apoptosis signaling to suppress MPM and HBC growth in part by activating novel transducers of apoptosis. This pilot study has paved way for further in-depth analysis of the downstream target molecules associated with presensitization of mesothelioma cells in finding effective therapeutic treatment options for both mesothelioma and recalcitrant breast cancers.",
keywords = "Apoptosis, Bortezomib (Velcade), Gene expression, Malignant pleural mesothelioma",
author = "Ying Wang and Rishi, {Arun K.} and Puliyappadamba, {Vineshkumar T.} and Sunita Sharma and Huanjie Yang and Adi Tarca and Dou, {Q. Ping} and Fulvio Lonardo and Ruckdeschel, {John C.} and Pass, {Harvey I.} and Anil Wali",
year = "2010",
month = "8",
day = "1",
doi = "10.1007/s00280-009-1181-8",
language = "English (US)",
volume = "66",
pages = "455--466",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "3",

}

TY - JOUR

T1 - Targeted proteasome inhibition by Velcade induces apoptosis in human mesothelioma and breast cancer cell lines

AU - Wang, Ying

AU - Rishi, Arun K.

AU - Puliyappadamba, Vineshkumar T.

AU - Sharma, Sunita

AU - Yang, Huanjie

AU - Tarca, Adi

AU - Dou, Q. Ping

AU - Lonardo, Fulvio

AU - Ruckdeschel, John C.

AU - Pass, Harvey I.

AU - Wali, Anil

PY - 2010/8/1

Y1 - 2010/8/1

N2 - Introduction: Thoracic malignancies and human breast cancer (HBC) continue to be aggressive solid tumors that are poor responders to the existing conventional standard chemotherapeutic approaches. Malignant pleural mesothelioma (MPM) is an asbestos-related tumor of the thoracic pleura that lacks effective treatment options. Altered ubiquitin proteasome pathway is frequently encountered in many malignancies including HBC and MPM and thus serves as an important target for therapeutic intervention strategies. Although proteasome inhibitor Velcade (Bortezomib) has been under clinical investigation for a number of cancers, limited preclinical studies with this agent have thus far been conducted in HBC and MPM malignancies. Purpose: To study the biological and molecular responses of MPM and HBC cells to Velcade treatments, and to identify mechanisms involved in transducing growth inhibitory effects of this agent. Methods: Flow-cytometric analyses coupled with western immunoblotting and gene-array methodologies were utilized to determine mechanisms of Velcade-dependent growth suppression of five MPM (H2595, H2373, H2452, H2461, and H2714) and two breast cancer (MDA MB-468, SKBR-3) cell lines. Results: Our data revealed significant reduction in cell growth properties that were dose and time dependent. Velcade treatment resulted in G2M phase arrest, increased expression of cyclin-dependent kinase inhibitor p21 and pro-apoptotic protein Bax. Pretreatment of mesothelioma cells with Velcade showed synergistic effect with cisplatin combination regimens. High-throughput gene expression profiling among Velcade treated and untreated mesothelioma cell lines resulted in identification of novel transducers of apoptosis such as CARP-1, XAF1, and Troy proteins. Conclusions: Velcade targets cell cycle and apoptosis signaling to suppress MPM and HBC growth in part by activating novel transducers of apoptosis. This pilot study has paved way for further in-depth analysis of the downstream target molecules associated with presensitization of mesothelioma cells in finding effective therapeutic treatment options for both mesothelioma and recalcitrant breast cancers.

AB - Introduction: Thoracic malignancies and human breast cancer (HBC) continue to be aggressive solid tumors that are poor responders to the existing conventional standard chemotherapeutic approaches. Malignant pleural mesothelioma (MPM) is an asbestos-related tumor of the thoracic pleura that lacks effective treatment options. Altered ubiquitin proteasome pathway is frequently encountered in many malignancies including HBC and MPM and thus serves as an important target for therapeutic intervention strategies. Although proteasome inhibitor Velcade (Bortezomib) has been under clinical investigation for a number of cancers, limited preclinical studies with this agent have thus far been conducted in HBC and MPM malignancies. Purpose: To study the biological and molecular responses of MPM and HBC cells to Velcade treatments, and to identify mechanisms involved in transducing growth inhibitory effects of this agent. Methods: Flow-cytometric analyses coupled with western immunoblotting and gene-array methodologies were utilized to determine mechanisms of Velcade-dependent growth suppression of five MPM (H2595, H2373, H2452, H2461, and H2714) and two breast cancer (MDA MB-468, SKBR-3) cell lines. Results: Our data revealed significant reduction in cell growth properties that were dose and time dependent. Velcade treatment resulted in G2M phase arrest, increased expression of cyclin-dependent kinase inhibitor p21 and pro-apoptotic protein Bax. Pretreatment of mesothelioma cells with Velcade showed synergistic effect with cisplatin combination regimens. High-throughput gene expression profiling among Velcade treated and untreated mesothelioma cell lines resulted in identification of novel transducers of apoptosis such as CARP-1, XAF1, and Troy proteins. Conclusions: Velcade targets cell cycle and apoptosis signaling to suppress MPM and HBC growth in part by activating novel transducers of apoptosis. This pilot study has paved way for further in-depth analysis of the downstream target molecules associated with presensitization of mesothelioma cells in finding effective therapeutic treatment options for both mesothelioma and recalcitrant breast cancers.

KW - Apoptosis

KW - Bortezomib (Velcade)

KW - Gene expression

KW - Malignant pleural mesothelioma

UR - http://www.scopus.com/inward/record.url?scp=77954678999&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954678999&partnerID=8YFLogxK

U2 - 10.1007/s00280-009-1181-8

DO - 10.1007/s00280-009-1181-8

M3 - Article

VL - 66

SP - 455

EP - 466

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 3

ER -