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Article: p21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients

Titlep21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patients
Authors
KeywordsPrognostic marker
Therapeutic target
Issue Date2010
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2010, v. 107 n. 43, p. 18622-18627 How to Cite?
Abstract
Ovarian 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.
Persistent Identifierhttp://hdl.handle.net/10722/137198
ISSN
2013 Impact Factor: 9.809
PubMed Central ID
ISI Accession Number ID
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.).

References

 

Author Affiliations
  1. The University of Hong Kong
  2. Karolinska Institutet
DC FieldValueLanguage
dc.contributor.authorSiu, MKYen_HK
dc.contributor.authorChan, HYen_HK
dc.contributor.authorKong, DSHen_HK
dc.contributor.authorWong, ESYen_HK
dc.contributor.authorWong, OGWen_HK
dc.contributor.authorNgan, HYSen_HK
dc.contributor.authorTam, KFen_HK
dc.contributor.authorZhang, Hen_HK
dc.contributor.authorLi, Zen_HK
dc.contributor.authorChan, QKYen_HK
dc.contributor.authorTsao, SWen_HK
dc.contributor.authorStrömblad, Sen_HK
dc.contributor.authorCheung, ANYen_HK
dc.date.accessioned2011-08-26T14:18:39Z-
dc.date.available2011-08-26T14:18:39Z-
dc.date.issued2010en_HK
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2010, v. 107 n. 43, p. 18622-18627en_HK
dc.identifier.issn0027-8424en_HK
dc.identifier.urihttp://hdl.handle.net/10722/137198-
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.en_HK
dc.languageengen_US
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_HK
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_HK
dc.subjectPrognostic markeren_HK
dc.subjectTherapeutic targeten_HK
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.titlep21-activated kinase 4 regulates ovarian cancer cell proliferation, migration, and invasion and contributes to poor prognosis in patientsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0027-8424&volume=107&issue=43&spage=18622&epage=18627&date=2010&atitle=p21-activated+kinase+4+regulates+ovarian+cancer+cell+proliferation,+migration,+and+invasion+and+contributes+to+poor+prognosis+in+patients-
dc.identifier.emailSiu, MKY: mkysiu@hkucc.hku.hken_HK
dc.identifier.emailNgan, HYS: hysngan@hkucc.hku.hken_HK
dc.identifier.emailTsao, SW: gswtsao@hku.hken_HK
dc.identifier.emailCheung, ANY: anycheun@hkucc.hku.hken_HK
dc.identifier.authoritySiu, MKY=rp00275en_HK
dc.identifier.authorityNgan, HYS=rp00346en_HK
dc.identifier.authorityTsao, SW=rp00399en_HK
dc.identifier.authorityCheung, ANY=rp00542en_HK
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1073/pnas.0907481107en_HK
dc.identifier.pmid20926745en_HK
dc.identifier.pmcidPMC2972956-
dc.identifier.scopuseid_2-s2.0-78649880786en_HK
dc.identifier.hkuros191093en_US
dc.identifier.hkuros192465en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-78649880786&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume107en_HK
dc.identifier.issue43en_HK
dc.identifier.spage18622en_HK
dc.identifier.epage18627en_HK
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000283677400072-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridSiu, MKY=24924018400en_HK
dc.identifier.scopusauthoridChan, HY=26024081600en_HK
dc.identifier.scopusauthoridKong, DSH=36113859000en_HK
dc.identifier.scopusauthoridWong, ESY=23101622300en_HK
dc.identifier.scopusauthoridWong, OGW=7004813981en_HK
dc.identifier.scopusauthoridNgan, HYS=34571944100en_HK
dc.identifier.scopusauthoridTam, KF=35622901400en_HK
dc.identifier.scopusauthoridZhang, H=13407674300en_HK
dc.identifier.scopusauthoridLi, Z=7409078039en_HK
dc.identifier.scopusauthoridChan, QKY=8390404100en_HK
dc.identifier.scopusauthoridTsao, SW=7102813116en_HK
dc.identifier.scopusauthoridStrömblad, S=6701556442en_HK
dc.identifier.scopusauthoridCheung, ANY=54927484100en_HK

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