YB-1 is upregulated during prostate cancer tumor progression and increases P-glycoprotein activity.
BACKGROUND
Currently, the main obstacle to curing advanced prostate cancer is development of androgen independence (AI), where malignant cells acquire the ability to survive in the absence of androgens. Our initial experimental approach used cDNA microarrays to characterize changes in gene expression in the LNCaP human prostate tumor model during progression to AI. The transcription factor Y-box binding protein (YB-1) was shown to be one of the genes upregulated. We focused on increased YB-1 expression during progression in clinical specimens, and further examined one of its downstream targets, P-glycoprotein (P-gp).


METHODS
Northern blot analysis was performed on LNCaP tumor series, as well as immunohistochemical analyses of human prostate cancer tissue samples. YB-1 was transiently transfected and transport analysis were performed to analyze P-gp efflux activity.


RESULTS
YB-1 expression is markedly increased during benign to malignant transformation and further following androgen ablation. In addition, increased YB-1 expression after castration in the LNCaP model is linked to upregulation of P-gp. We demonstrate that YB-1 upregulates P-gp activity resulting in a 40% intracellular decrease in the P-gp substrate vinblastine. We have also found that P-gp increases the efflux of the endogenous androgen, dihydrotestosterone (DHT), from prostate cells and leads to decreased androgen regulated gene expression.


CONCLUSIONS
We hypothesize that early in prostate cancer progression, increased expression of YB-1 may increase P-gp activity which may in turn lower androgen levels in the prostate tumor cells. Suppression of androgen levels may activate cell survival pathways and lead to an adaptive survival advantage of androgen independent prostate cancer cells following androgen ablation therapy.
Giménez-Bonafé
Pepita
P
The Prostate Centre at Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
Fedoruk
Matthew N
MN
Whitmore
Tanis G
TG
Akbari
Majid
M
Ralph
Jody L
JL
Ettinger
Susan
S
Gleave
Martin E
ME
Nelson
Colleen C
CC
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000494:pharmacology*; D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology; D015152:Blotting, Northern; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis*; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051839:NFI Transcription Factors; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D014157:Transcription Factors / Q000096:biosynthesis*; D015854:Up-Regulation; D051840:Y-Box-Binding Protein 1
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000726:Androgen Antagonists; D000728:Androgens; D022762:CCAAT-Enhancer-Binding Proteins; D051839:NFI Transcription Factors; D014157:Transcription Factors; D051840:Y-Box-Binding Protein 1