The interaction of PKN3 with RhoC promotes malignant growth.
PKN3 is an AGC-family protein kinase implicated in growth of metastatic prostate cancer cells with phosphoinositide 3-kinase pathway deregulation. The molecular mechanism, however, by which PKN3 contributes to malignant growth and tumorigenesis is not well understood. Using orthotopic mouse tumor models, we now show that inducible knockdown of PKN3 protein not only blocks metastasis, but also impairs primary prostate and breast tumor growth. Correspondingly, overexpression of exogenous PKN3 in breast cancer cells further increases their malignant behavior and invasiveness in-vitro. Mechanistically, we demonstrate that PKN3 physically interacts with Rho-family GTPases, and preferentially with RhoC, a known mediator of tumor invasion and metastasis in epithelial cancers. Likewise, RhoC predominantly associates with PKN3 compared to its closely related PKN family members. Unlike the majority of Rho GTPases and PKN molecules, which are ubiquitously expressed, both PKN3 and RhoC show limited expression in normal tissues and become upregulated in late-stage malignancies. Since PKN3 catalytic activity is increased in the presence of Rho GTPases, the co-expression and preferential interaction of PKN3 and RhoC in tumor cells are functionally relevant. Our findings provide novel insight into the regulation and function of PKN3 and suggest that the PKN3-RhoC complex represents an attractive therapeutic target in late-stage malignancies.
Oncology Research Unit, Pfizer Oncology, Pfizer Worldwide Research and Development, Pearl River, NY 10965, USA. Keziban.Unsal-Kacmaz@Pfizer.com
Keziban
K
Unsal-Kacmaz
Shoba
S
Ragunathan
Edward
E
Rosfjord
Stephen
S
Dann
Erik
E
Upeslacis
Mary
M
Grillo
Richard
R
Hernandez
Fiona
F
Mack
Anke
A
Klippel
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004318:Doxycycline / Q000627:therapeutic use; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D000075024:rhoC GTP-Binding Protein
D034741:RNA, Small Interfering; C061570:protein kinase N; D011493:Protein Kinase C; C512911:Rhoc protein, mouse; D018631:ras Proteins; D000075024:rhoC GTP-Binding Protein; D004318:Doxycycline