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Article: p21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients
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Titlep21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients
 
AuthorsSiu, MKY1
Chan, HY1
Kong, DSH1
Wong, ESY1
Wong, OGW1
Ngan, HYS1
Tam, KF1
Zhang, H2
Li, Z2
Chan, QKY1
Tsao, SW1
Strömblad, S2
Cheung, ANY1
 
KeywordsPrognostic marker
Therapeutic target
 
Issue Date2010
 
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
 
CitationProceedings Of The National Academy Of Sciences Of The United States Of America, 2010, v. 107 n. 43, p. 18622-18627 [How to Cite?]
DOI: http://dx.doi.org/10.1073/pnas.0907481107
 
AbstractOvarian cancer is a lethal gynecological malignancy, and to improve survival, it is important to identify novel prognostic and therapeutic targets. In this study, we present a role for p21-activated kinase 4 (Pak4) in ovarian cancer progression. We show a significant association between increased expression of Pak4 and its activated form, phosphorylated (p)-Pak4 Ser 474, with metastasis of ovarian cancers, shorter overall and disease-free survival, advanced stage and high-grade cancers, serous/clear cell histological subtypes, and reduced chemosensitivity. Pak4 overexpression was also observed in ovarian cancer cell lines. Pak4 and p-Pak4 expression were detected both in the nucleus and cytoplasm of ovarian cancer cells, in vitro as well as in vivo. Stable knockdown of Pak4 in ovarian cancer cell lines led to reduced cell migration, invasion, and proliferation, along with reduced c-Src, ERK1/2, and epidermal growth factor receptor (EGFR) activation and decreased matrix metalloproteinase 2 (MMP2) expression. Conversely, Pak4 overexpression promoted ovarian cancer cell migration and invasion in a c-Src, MEK-1, MMP2, and kinase-dependent-manner, and induced cell proliferation through the Pak4/c-Src/EGFR pathway that controls cyclin D1 and CDC25A expression. Stable knockdown of Pak4 also impeded tumor growth and dissemination in nude mice. This report reveals the association between Pak4 and important clinicopathologic parameters, suggesting Pak4 to be a significant prognostic marker and potential therapeutic molecular target in ovarian cancer. The implied possible cross-talk between Pak4 and EGFR suggests the potential of dual targeting of EGFR and Pak4 as a unique therapeutic approach for cancer therapy.
 
ISSN0027-8424
2013 Impact Factor: 9.809
 
DOIhttp://dx.doi.org/10.1073/pnas.0907481107
 
PubMed Central IDPMC2972956
 
ISI Accession Number IDWOS:000283677400072
Funding AgencyGrant Number
Hong Kong Anti-Cancer Society
Hong Kong Research Grants CouncilHKU 750306M
University of Hong Kong
Center for Biosciences
Swedish Cancer Society
Swedish Research Council
Funding Information:

We thank the Faculty Core Facility, Dr. Chi Keung Lau for providing valuable advice and technical help for in vivo studies and Dr. Kelvin Chan for his valuable comments. This work was supported by the Hong Kong Anti-Cancer Society Grant (to M.K.Y.S.), Hong Kong Research Grants Council Grant (HKU 750306M) (to A.N.Y.C.), the University of Hong Kong Seed Funding and Small Project Funding (to A.N.Y.C. and M.K.Y.S.), and the Center for Biosciences, the Swedish Cancer Society, and the Swedish Research Council Grants (to S.S.).

 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorSiu, MKY
 
dc.contributor.authorChan, HY
 
dc.contributor.authorKong, DSH
 
dc.contributor.authorWong, ESY
 
dc.contributor.authorWong, OGW
 
dc.contributor.authorNgan, HYS
 
dc.contributor.authorTam, KF
 
dc.contributor.authorZhang, H
 
dc.contributor.authorLi, Z
 
dc.contributor.authorChan, QKY
 
dc.contributor.authorTsao, SW
 
dc.contributor.authorStrömblad, S
 
dc.contributor.authorCheung, ANY
 
dc.date.accessioned2011-08-26T14:18:39Z
 
dc.date.available2011-08-26T14:18:39Z
 
dc.date.issued2010
 
dc.description.abstractOvarian cancer is a lethal gynecological malignancy, and to improve survival, it is important to identify novel prognostic and therapeutic targets. In this study, we present a role for p21-activated kinase 4 (Pak4) in ovarian cancer progression. We show a significant association between increased expression of Pak4 and its activated form, phosphorylated (p)-Pak4 Ser 474, with metastasis of ovarian cancers, shorter overall and disease-free survival, advanced stage and high-grade cancers, serous/clear cell histological subtypes, and reduced chemosensitivity. Pak4 overexpression was also observed in ovarian cancer cell lines. Pak4 and p-Pak4 expression were detected both in the nucleus and cytoplasm of ovarian cancer cells, in vitro as well as in vivo. Stable knockdown of Pak4 in ovarian cancer cell lines led to reduced cell migration, invasion, and proliferation, along with reduced c-Src, ERK1/2, and epidermal growth factor receptor (EGFR) activation and decreased matrix metalloproteinase 2 (MMP2) expression. Conversely, Pak4 overexpression promoted ovarian cancer cell migration and invasion in a c-Src, MEK-1, MMP2, and kinase-dependent-manner, and induced cell proliferation through the Pak4/c-Src/EGFR pathway that controls cyclin D1 and CDC25A expression. Stable knockdown of Pak4 also impeded tumor growth and dissemination in nude mice. This report reveals the association between Pak4 and important clinicopathologic parameters, suggesting Pak4 to be a significant prognostic marker and potential therapeutic molecular target in ovarian cancer. The implied possible cross-talk between Pak4 and EGFR suggests the potential of dual targeting of EGFR and Pak4 as a unique therapeutic approach for cancer therapy.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2010, v. 107 n. 43, p. 18622-18627 [How to Cite?]
DOI: http://dx.doi.org/10.1073/pnas.0907481107
 
dc.identifier.doihttp://dx.doi.org/10.1073/pnas.0907481107
 
dc.identifier.eissn1091-6490
 
dc.identifier.epage18627
 
dc.identifier.hkuros191093
 
dc.identifier.hkuros192465
 
dc.identifier.isiWOS:000283677400072
Funding AgencyGrant Number
Hong Kong Anti-Cancer Society
Hong Kong Research Grants CouncilHKU 750306M
University of Hong Kong
Center for Biosciences
Swedish Cancer Society
Swedish Research Council
Funding Information:

We thank the Faculty Core Facility, Dr. Chi Keung Lau for providing valuable advice and technical help for in vivo studies and Dr. Kelvin Chan for his valuable comments. This work was supported by the Hong Kong Anti-Cancer Society Grant (to M.K.Y.S.), Hong Kong Research Grants Council Grant (HKU 750306M) (to A.N.Y.C.), the University of Hong Kong Seed Funding and Small Project Funding (to A.N.Y.C. and M.K.Y.S.), and the Center for Biosciences, the Swedish Cancer Society, and the Swedish Research Council Grants (to S.S.).

 
dc.identifier.issn0027-8424
2013 Impact Factor: 9.809
 
dc.identifier.issue43
 
dc.identifier.openurl
 
dc.identifier.pmcidPMC2972956
 
dc.identifier.pmid20926745
 
dc.identifier.scopuseid_2-s2.0-78649880786
 
dc.identifier.spage18622
 
dc.identifier.urihttp://hdl.handle.net/10722/137198
 
dc.identifier.volume107
 
dc.languageeng
 
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
 
dc.publisher.placeUnited States
 
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshCell Line, Tumor
 
dc.subject.meshCytoplasm - enzymology
 
dc.subject.meshDNA Primers - genetics
 
dc.subject.meshOvarian Neoplasms - enzymology - genetics - pathology
 
dc.subject.meshp21-Activated Kinases - antagonists and inhibitors - genetics - physiology
 
dc.subjectPrognostic marker
 
dc.subjectTherapeutic target
 
dc.titlep21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong
  2. Karolinska Institutet