RGD Reference Report - Modulation of p21-activated kinase 1 alters the behavior of renal cell carcinoma. - Rat Genome Database

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Modulation of p21-activated kinase 1 alters the behavior of renal cell carcinoma.

Authors: O'Sullivan, GC  Tangney, M  Casey, G  Ambrose, M  Houston, A  Barry, OP 
Citation: O'Sullivan GC, etal., Int J Cancer. 2007 Nov 1;121(9):1930-40.
RGD ID: 2299159
Pubmed: PMID:17621631   (View Abstract at PubMed)
DOI: DOI:10.1002/ijc.22893   (Journal Full-text)

The p21-activated kinase 1 (Pak1) is a serine/threonine kinase whose activity is regulated by both Rho GTPases and AGC kinase family members. It plays a role in cytoskeletal remodeling and cell motility as well as cell proliferation, angiogenesis, tumorigenesis and metastasis. An involvement of Pak1 in renal cell carcinoma (RCC), which remains highly refractory to chemotherapy and radiotherapy, remains to be investigated. Pak1 expression, phosphorylation and kinase activity were examined in RCC cell lines and human tissue from normal and renal carcinoma. We report increased Pak1 expression and constitutive activity in the membrane and nucleus but not the cytoplasm of resected human RCC. To study a role for Pak1 in RCC, we developed 786-0 clones that expressed either a kinase-active Pak1L83,L86 2 different Pak1 dominant negative mutants, Pak1R299 and Pak1L83,L86,R299 or Pak1 siRNA. The expression of Pak1L83,L86 increased 786-0 proliferation, motility and anchorage independent growth, while the dominant negative mutants and Pak1 siRNA abrogated these effects. In addition, Pak1L83,L86 conferred resistance to 5-fluorouracil with a 40%+/-10% increase in cell viability. Conversely, Pak1L83,L86,R299, Pak1R299 and Pak1 siRNA conferred sensitivity with a 65.2%+/-5.5%, 69.2%+/-3.3% and 73.0%+/-8.4% loss in viability, respectively. Finally, Pak1 plays a role in renal tumor growth in vivo. Only 33% of mice developed tumors in the Pak1L83,L86,R299 group and no tumors developed from Pak1R299 cell challenge. Together these findings point to Pak1 as an exciting target for therapy of renal cancer, which remains highly refractory to existing treatments.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
renal cell carcinoma  IEP 2299159protein:increased expression:kidneyRGD 
renal cell carcinoma  IMP 2299159 RGD 
renal cell carcinoma  ISOPAK1 (Homo sapiens)2299159; 2299159protein:increased expression:kidneyRGD 

Objects Annotated

Genes (Rattus norvegicus)
Pak1  (p21 (RAC1) activated kinase 1)

Genes (Mus musculus)
Pak1  (p21 (RAC1) activated kinase 1)

Genes (Homo sapiens)
PAK1  (p21 (RAC1) activated kinase 1)


Additional Information