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KIF15 Promotes Progression of Castration Resistant Prostate Cancer by Activating EGFR Signaling Pathway.

ABSTRACT: Castration-resistant prostate cancer (CRPC) continues to be a major clinical problem and its underlying mechanisms are still not fully understood. The epidermal growth factor receptor (EGFR) activation is an important event that regulates mitogenic signaling. EGFR signaling plays an important role in the transition from androgen dependence to castration-resistant state in prostate cancer (PCa). Kinesin family member 15 (KIF15) has been suggested to be overexpressed in multiple malignancies. Here, we demonstrate that KIF15 expression is elevated in CRPC. We show that KIF15 contributes to CRPC progression by enhancing the EGFR signaling pathway, which includes complex network intermediates such as mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. In CRPC tumors, increased expression of KIF15 is positively correlated with EGFR protein level. KIF15 binds to EGFR, and prevents EGFR proteins from degradation in a Cdc42-dependent manner. These findings highlight the key role of KIF15 in the development of CRPC and rationalize KIF15 as a potential therapeutic target.

SUBMITTER: Gao L

PROVIDER: S-EPMC8599584 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAlthough recent progress has been made in treating castration resistant prostate cancer, the interplay of signaling pathways which enable castration resistant growth is incompletely understood. A data driven, multivariate approach, was used in this study to predict prostate cancer cell survival based on the phosphorylation levels of key proteins in PC3, LNCaP, and MDA-PCa-2b cell lines in response to EGF, IGF1, IL6, TNF?, dihydrotestosterone, and docetaxel treatment.MethodsThe prostate cancer cell lines were treated with ligands or inhibitors, cell lyates were collected, and the amount of phosphoprotein quantified using 384 well ELISA assays. In separate experiments, relative cell viability was determined using an MTT assay. Normalized data was imported into Matlab where regression analysis was performed.ResultsBased on a linear model developed using partial least squares regression, p-Erk1/2 was found to correlate with castration resistant survival along with p-RPS6, and this model was determined to have a leave-one-out cross validated R2 value of 0.61. The effect of androgen on the phosphoproteome was examined, and increases in PI3K related phosphoproteins (p-Akt, p-RPS6, and p-GSK3) were observed which accounted for the majority of the significant increase in androgen-mediated cell survival. Simultaneous inhibition of the PI3K pathway and treatment with androgen resulted in a non-significant increase in survival. Given the strong effect of PI3K related signaling in enabling castration resistant survival, the specific effect of mTor versus complete inhibition was examined using targeted inhibitors. It was determine that mTor inhibition accounts for 52% of the effect of complete PI3K inhibition on cell survival. The differences in signaling between the cell lines were explored it was observed that MDA-PCa-2b exhibited far less activation of p-Erk in response to varying treatments, explaining one of the reasons for the lack of castration resistance.ConclusionIn this work, regression analysis to the phosphoproteome was used to illustrate the sources of castration resistance between the cell lines including reduced p-Erk signaling in MDA-PCa-2b and variations in p-JNK across the cell lines, as well as studying the signaling pathways which androgen acts through, and determining the response to treatment with targeted inhibitors.

Project description:BackgroundAs deregulation of androgen receptor (AR) signaling target genes is associated with tumorigenesis and the development of prostate cancer (PCa), AR signaling is the primary therapeutic target for PCa. Although patients initially responses to first-line androgen deprivation therapies (ADTs), most of them with advanced PCa progress to lethal castration-resistant prostate cancer (CRPC). Recent studies have suggested the molecular mechanisms by which AR elicit the robust up-regulation of the FKBP51 gene. We suggest that restored expression of FKBP51 gene, modulated by androgen receptor splicing variant 7 (AR-V7) which replaces full length androgen receptor (AR-FL) in androgen ablation status, promotes CRPC progression through activating NF-κB signaling.MethodsImmunohistochemistry assays were used to detect the expression of AR-V7, FKBP51 and NF-κB signaling correlated proteins in CRPC tissues. An androgen ablation resistant PCa cell line model established by Long-term culturing in androgen depleted medium, named androgen-independent LNCaP (LNCaP-AI) cells, were used to dynamically monitor FKBP51 expression during the process of androgen dependent PCa cells transforming into androgen-independent cells, as well as its association with NF-κB signal pathway. LNCaP-AI cell line was determined to express AR-V7 protein continuously. Luciferase reporter assays and DNA pull down were used to determine the association between AR-V7 and FKBP51.ResultsOur results suggested that CRPC patients with AR-V7 high expression tend to have higher expression of FKBP51 and enhanced NF-κB signaling compared with AR-V7 negative patients. Knockdown of AR-V7 or FKBP51 in LNCaP-AI cells attenuated the level of p-NF-κB (Ser536) and androgen-resistant cells growth. Luciferase reporter assays and DNA pull down results indicated that FKBP51 was transcriptionally promoted by AR-V7 in absence of androgen, which enhanced NF-κB signaling.ConclusionsBecause of upregulation of AR-V7 in androgen-independent PCa cells, increasing of FKBP51 induced NF-κB signaling, leading to progression of CRPC.

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KIF15 Promotes Progression of Castration Resistant Prostate Cancer by Activating EGFR Signaling Pathway.

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