Cathepsin D acts as an essential mediator to promote malignancy of benign prostatic epithelium

Abstract

BACKGROUND Stromal-epithelial interactions are important in both development and prostate cancer. Stromal changes have been shown to be powerful prognostic indicators of prostate cancer progression and of patient death helping to define lethal versus indolent phenotypes. The specific molecular underpinnings of these interactions are incompletely understood. We investigated whether stromal cathepsin D (CathD) overexpression affects prostate tumorigenesis through a paracrine mechanism. METHODS Normal prostate fibroblasts (NPF) were retrovirally transduced to overexpress cyclin D1 (CD1) cells were designated NPFCD1. Cathepsin D expression was knocked down using shRNA in cancer associated fibroblasts (CAF) and NPFCD1. We analyzed these stromal cell lines using immunohistochemistry, Western blot, and tissue recombination. RESULTS An examination of human prostate tissue revealed significantly increased stromal staining of CathD in malignant prostate tissue. Overexpression of CD1 in normal prostate fibroblasts (NPFCD1) produced a phenotype similar to, but more moderate than, CAF in a tissue recombination model. Knockdown studies revealed that CathD is required for NPFCD1 motility and invasive growth in vitro. BPH-1 cell proliferation was found to be induced when cultured with NPFCD1 conditioned medium, this effect was inhibited when CathD was knocked down in NPFCD1 cells. Overexpression of CathD in prostate stromal cells induced malignancy in adjacent epithelium, and this transformation was inhibited when stromal CathD expression was knocked down in CAF. CONCLUSIONS The study presented here demonstrates increased CathD expression is seen in human CAF. The upregulation of CD1 results in concomitant increases in CathD expression. Elevated CathD expression in the stroma contributes to tumor promotion.

Honokiol exhibits enhanced antitumor effects with chloroquine by inducing cell death and inhibiting autophagy in human non-small cell lung cancer cells

“…LC3 is the most widely used biomarker of autophagosome formation with the capability of inducing autophagy (27,28). HCQ inhibited autophagy through augumenting p62 and LC3-Ⅱ proteins (29). In our experiment, we found that HNK increased the expression levels of p62 and LC3-Ⅱ, showing that HNK inhibited autophagy in the NSCLC cells via a similar mechanism to CQ by disrupting autolysosome function.…”

Influence of stromal–epithelial interactions on androgen action

“…Normal prostate fibroblasts exhibiting cyclin D1 overexpression have been shown to induce a malignant transformation of the BPH1 epithelial cell line in vivo (He et al 2007). Cathepsin D is required for the contribution of cyclin D1 to NPF malignancy, and overexpression of cathepsin D in the stroma promotes tumor growth (Pruitt et al 2013). This is only one of the many examples of genetic alterations promoting tumorigenesis in CAFs.…”

Blood mRNA Expression Profiling Predicts Survival in Patients Treated with Tremelimumab

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