PTRF/cavin-1 neutralizes non-caveolar caveolin-1 microdomains in prostate cancer.
Caveolin-1 has a complex role in prostate cancer and has been suggested to be a potential biomarker and therapeutic target. As mature caveolin-1 resides in caveolae, invaginated lipid raft domains at the plasma membrane, caveolae have been suggested as a tumor-promoting signaling platform in prostate cancer. However, caveola formation requires both caveolin-1 and cavin-1 (also known as PTRF; polymerase I and transcript release factor). Here, we examined the expression of cavin-1 in prostate epithelia and stroma using tissue microarray including normal, non-malignant and malignant prostate tissues. We found that caveolin-1 was induced without the presence of cavin-1 in advanced prostate carcinoma, an expression pattern mirrored in the PC-3 cell line. In contrast, normal prostate epithelia expressed neither caveolin-1 nor cavin-1, while prostate stroma highly expressed both caveolin-1 and cavin-1. Utilizing PC-3 cells as a suitable model for caveolin-1-positive advanced prostate cancer, we found that cavin-1 expression in PC-3 cells inhibits anchorage-independent growth, and reduces in vivo tumor growth and metastasis in an orthotopic prostate cancer xenograft mouse model. The expression of α-smooth muscle actin in stroma along with interleukin-6 (IL-6) in cancer cells was also decreased in tumors of mice bearing PC-3-cavin-1 tumor cells. To determine whether cavin-1 acts by neutralizing caveolin-1, we expressed cavin-1 in caveolin-1-negative prostate cancer LNCaP and 22Rv1 cells. Caveolin-1 but not cavin-1 expression increased anchorage-independent growth in LNCaP and 22Rv1 cells. Cavin-1 co-expression reversed caveolin-1 effects in caveolin-1-positive LNCaP cells. Taken together, these results suggest that caveolin-1 in advanced prostate cancer is present outside of caveolae, because of the lack of cavin-1 expression. Cavin-1 expression attenuates the effects of non-caveolar caveolin-1 microdomains partly via reduced IL-6 microenvironmental function. With circulating caveolin-1 as a potential biomarker for advanced prostate cancer, identification of the molecular pathways affected by cavin-1 could provide novel therapeutic targets.
The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Queensland, Australia.
H
H
Moon
1] Discipline of Pathology, School of Medicine and Molecular Medicine Research Group, University of Western Sydney, Sydney, New South Wales, Australia [2] Department of Anatomical Pathology, Liverpool Hospital, Sydney, New South Wales, Australia.
C S
CS
Lee
The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Queensland, Australia.
K L
KL
Inder
1] Discipline of Pathology, School of Medicine and Molecular Medicine Research Group, University of Western Sydney, Sydney, New South Wales, Australia [2] Department of Anatomical Pathology, Liverpool Hospital, Sydney, New South Wales, Australia.
S
S
Sharma
1] The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Queensland, Australia [2] School of Veterinary Science, The University of Queensland, Brisbane, Queensland, Australia.
E
E
Choi
The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Queensland, Australia.
D M
DM
Black
Queensland Facility for Advanced Bioinformatics, The University of Queensland, Brisbane, Queensland, Australia.
K-A
KA
Lê Cao
School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
C
C
Winterford
Mater Research, Translational Research Institute, Brisbane, Queensland, Australia.
J I
JI
Coward
Australian Prostate Cancer Research Centre-Queensland and Institute for Biomedical Health & Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, Queensland, Australia.
M T
MT
Ling
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
D J
DJ
Craik
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
R G
RG
Parton
Australian Prostate Cancer Research Centre-Queensland and Institute for Biomedical Health & Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, Queensland, Australia.
P J
PJ
Russell
The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, Queensland, Australia.
M M
MM
Hill
D000199:Actins / Q000378:metabolism; D000368:Aged; D000818:Animals; D051242:Caveolin 1 / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism
C541116:ACTA2 protein, human; D000199:Actins; C497835:CAVIN1 protein, human; D051242:Caveolin 1; D015850:Interleukin-6; D016601:RNA-Binding Proteins; D011944:Receptors, Androgen; D051057:Proto-Oncogene Proteins c-akt