RAGE (receptor for advanced glycation end-product) is thought to be associated with metastasis and poor prognosis of various types of cancer. However, RAGE is constitutively expressed in the normal lung and down-regulated in cancerous lung, while the opposite evidence shows that RAGE-mediated signaling contributes to the tumorigenesis of lung cancer. Therefore, the role of RAGE in lung cancer progression is still unclear to be further investigated. In this study, RAGE-overexpressed stable clones of human lung cancer A549 cells and two local lung adenocarcinoma cell lines CL1-0 and CL1-5 were utilized to verify the effect of RAGE on lung cancer cells while the in vivo xenograft animal model was further performed to evaluate the role of RAGE in the progression of lung cancer. The growth of A549 cells was inhibited by RAGE overexpression. p53-dependent p21 CIP1 expression contributed to RAGE-induced growth inhibition by suppressing CDK2 kinase activity and retinoblastoma protein (RB) phosphorylation in vitro. On the other hand, RAGE overexpression promoted migration, invasion, and mesenchymal features of lung adenocarcinoma cells through ERK signaling. Furthermore, an in vivo xenograft experiment indicated that RAGE promoted the metastasis of lung cancer cells with p21 CIP1 up-regulation, ERK activation, and the changes of EMT markers. Regarding to the involvement of tumor-associated macrophage (TAM) in the microenvironment, we monitored the expressions of TAM markers including CD68 and CD163 as well as angiogenesis marker CD31 in xenograft slice. The data showed that RAGE might induce the accumulation of TAM in lung cancer cells and further accelerate the in vivo tumor growth. In summary, our study provides evidence indicating the distinct in vitro and in vivo effects of RAGE and related mechanisms on tumor growth and metastasis, which shed light on the oncogenic role of RAGE in lung cancer.

Prostate cancer (PCa) is a major diagnosed cancer among men globally, and about 20% of patients develop metastatic prostate cancer (mPCa) in the initial diagnosis. PCa is a typical androgen-dependent disease; thus, hormonal therapy is commonly used as a standard care for mPCa by inhibiting androgen receptor (AR) activities, or androgen metabolism. Inevitably, almost all PCa will acquire resistance and become castration-resistant PCa (CRPC) that is associated with AR gene mutations or amplification, the presence of AR variants, loss of AR expression toward neuroendocrine phenotype, or other hormonal receptors. Treating CRPC poses a great challenge to clinicians. Research efforts in the last decade have come up with several new anti-androgen agents to prolong overall survival of CRPC patients. In addition, many potential targeting agents have been at the stage of being able to translate many preclinical discoveries into clinical practices. At this juncture, it is important to highlight the emerging strategies including small-molecule inhibitors to AR variants, DNA repair enzymes, cell survival pathway, neuroendocrine differentiation pathway, radiotherapy, CRPC-specific theranostics and immune therapy that are underway or have recently been completed.

No abstract

<div>Abstract<p>The significance of Cdk5 in cell-cycle control and cancer biology has gained increased attention. Here we report the inverse correlation between the protein levels of Cdk5 and p21^CIP1 from cell-based and clinical analysis. Mechanistically, we identify that Cdk5 overexpression triggers the proteasome-dependent degradation of p21^CIP1 through a S130 phosphorylation in a Cdk2-independent manner. Besides, the evidence from cell-based and clinical analysis shows that Cdk5 primarily regulates nuclear p21^CIP1 protein degradation. S130A-p21^CIP1 mutant enables to block either its protein degradation or the increase of cancer cell growth caused by Cdk5. Notably, Cdk5-triggered p21^CIP1 targeting primarily appears in S-phase, while Cdk5 overexpression increases the activation of Cdk2 and its interaction with DNA polymerase δ. The <i>in vivo</i> results show that Cdk2 might play an important role in the downstream signaling to Cdk5. In summary, these findings suggest that Cdk5 in a high expression status promotes cancer growth by directly and rapidly releasing p21^CIP1-dependent cell-cycle inhibition and subsequent Cdk2 activation, which illustrates an oncogenic role of Cdk5 potentially applied for future diagnosis and therapy. <i>Cancer Res; 76(23); 6888–900. ©2016 AACR</i>.</p></div>