Altered Endosome Biogenesis in Prostate Cancer Has Biomarker Potential

Abstract

Prostate cancer is the second most common form of cancer in males, affecting one in eight men by the time they reach the age of 70. Current diagnostic tests for prostate cancer have significant problems with both false negatives and false positives, necessitating the search for new molecular markers. A recent investigation of endosomal and lysosomal proteins revealed that the critical process of endosomal biogenesis might be altered in prostate cancer. Here, a panel of endosomal markers was evaluated in prostate cancer and non-malignant cells and a significant increase in gene and protein expression was found for early, but not late endosomal proteins. There was also a differential distribution of early endosomes, and altered endosomal traffic and signalling of the transferrin receptors (TFRC and TFR2) in prostate cancer cells. These findings support the concept that endosome biogenesis and function is altered in prostate cancer. Microarray analysis of a clinical cohort confirmed the altered endosomal gene expression observed in cultured prostate cancer cells. Furthermore, in prostate cancer patient tissue specimens, the early endosomal marker and adaptor protein APPL1 showed consistently altered basement membrane histology in the vicinity of tumours and concentrated staining within tumour masses. These novel observations on altered early endosome biogenesis provide a new avenue for prostate cancer biomarker investigation and suggest new methods for the early diagnosis and accurate prognosis of prostate cancer.

APPL1-Mediating Leptin Signaling Contributes to Proliferation and Migration of Cancer Cells

“…The previous studies have shown that APPL1 protein promotes invasion and progression of some cancer types by altering early endosome biogenesis [16, 25], provoking alternative TGFβ signaling pathways [15], modulating DNA repair [17], or promoting cell cycle progress [26]. In the present study, we found a novel mechanism of APPL1-directed proliferation and migration of cancer cells by positively regulating leptin signaling pathway.…”

Expression of APPL1 Is Correlated with Clinicopathologic Characteristics and Poor prognosis in Patients with Gastric Cancer

“…Expression of appl1 mrna was also higher in gc than in non-gc specimens (p = 0.009). Those results were similar to findings previously reported in prostate cancer 20 and breast cancer 12 .…”

APPL1 promotes the migration of gastric cancer cells by regulating Akt2 phosphorylation

“…In the present study, we focused on changes in APPL1 expression in gastric cancer and the effect of APPL1 on cancer cell metastasis. The results showed that APPL1 protein and mRNA were upregulated both in gastric carcinoma tissue and cultured cell lines, which were consistent with findings previously reported in prostate (8), breast (20) and gastric cancer (19).…”

“…Metastasis is the predominant cause of cancer-related mortality in gastric carcinogenesis and the mechanism of tumor metastasis is a multifactorial process associated with multiple genetic and epigenetic events. Previous studies have shown that adaptor proteins promote invasion and migration progression of some cancer types by altering early endosome biogenesis, which could have important implications for cancer cell biomarker release and intracellular signaling (3,7,8).…”

“…The recent discovery of altered adaptor proteins in cancer has identified a fundamental change involved in cell migration and invasion (6)(7)(8). Adaptor proteins are composed exclusively of domains and motifs that mediate molecular interactions, and can thereby link signaling proteins such as activated cellsurface receptors to downstream effectors.…”