KIF3a Promotes Proliferation and Invasion via Wnt Signaling in Advanced Prostate Cancer

Abstract

Aberrant activation of the Wnt/β-catenin signaling pathway is a critical event in advanced prostate cancer, but the genetic alterations which activate the Wnt signaling pathway in many other cancers are rarely observed in prostate cancer. Other molecular mechanisms that regulate the Wnt signaling pathway in prostate cancer remain to be identified. Here it is demonstrated that KIF3a, a subunit of kinesin-II motor protein, functions as an agonist of the Wnt signaling pathway in prostate cancer. KIF3a is up-regulated in the majority of human prostate cancer cell lines and primary tumor biopsies. The expression levels of KIF3a correlate with a higher Gleason score, TNM grade, and metastatic status of prostate cancer. Moreover, exogenous expression of KIF3a promoted cell growth in the benign prostate cells, whereas silencing KIF3a in cancer cells decreased cell proliferation, anchorage-independent cell growth, and cell migration/invasion. Mechanistically, KIF3a increases CK1-dependent DVL2 phosphorylation and β-catenin activation in prostate cancer cells, leading to transactivation of the Wnt signaling target genes such as Cyclin D1, HEF1, and MMP9. These findings support the notion that up-regulation of KIF3a is causal of aberrant activation of Wnt signaling in advanced prostate cancer through the KIF3a-DVL2-β-catenin axis. Implications Inactivation of KIF3a may improve survival of patients with advanced prostate cancer in which Wnt signaling is activated.

Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process

“…When fibroblasts differentiate into myofibroblast, the ability of synthesis ECM is enhanced and fibrosis proceeding is aggravated [36]. The importance of Wnt signaling in metastatic and invasive capacity is already demonstrated in many tumor cells [37,38]. Therefore, we used scarification essay and found that NSC668036 can remarkably depress the migration ability of fibroblasts.…”

Astrocyte elevated gene-1 promotes the proliferation and invasion of breast cancer cells by activating the Wnt/β-catenin signaling pathway

“…Bidwell et al (37) demonstrated that targeted c-Myc inhibitory polypeptides significantly suppressed breast cancer tumor growth in an orthotopic mouse model of breast cancer. Liu et al (38) identified that klf3a, a subunit of the kinesin-II motor protein, promotes cell proliferation and invasion via Wnt signaling in advanced prostate cancer, modulating cyclin D1 and c-Myc expression. It has been reported that the excessive production of MMP9, the major MMP, is associated with the metastasis of breast cancer.…”

Role of the LKB1/AMPK pathway in tumor invasion and metastasis of cancer cells (Review)

“…Thakur et al demonstrated that TGF-β upregulates the expression of Snail1 and increases the motility and invasiveness of human prostate cancer cells by activating the TRAF6/p38MAPK pathway (46). Apart from TGF-β signaling, other signal pathways including PI3K/AKT (47), NF-κB (48,49), Hedgehog (50), MAPK/ERK (51), p38MAPK (52) and Wnt/β-catenin (53,54) play important roles in tumor progression (Fig. 2).…”