Notch3 is activated by chronic hypoxia and contributes to the progression of human prostate cancer

Abstract

Prostate cancer is still the second cause of cancer-related death among men. Although patients with metastatic presentation have an ominous outcome, the vast majority of PCs are diagnosed at an early stage. Nonetheless, even among patients with clinically localized disease the outcome may vary considerably. Other than androgen sensitivity, little is known about which other signaling pathways are deranged in aggressive, localized cancers. The elucidation of such pathways may help to develop innovative therapies aimed at specific molecular targets. We report that in a hormone-sensitive prostate cancer cell line, LNCaP, Notch3 was activated by hypoxia and sustained cell proliferation and colony formation in soft agar. Hypoxia also modulated cellular cholesterol content and the number and size of lipid rafts, causing a coalescence of small rafts into bigger clusters; under this experimental condition Notch3 migrated from the non-raft into the raft compartment where it co-localized with the γ-secretase complex. We also looked at human prostate cancer biopsies and found that expression of Notch3 positively correlated with Gleason score and with expression of carbonic anhydrase IX, a marker of hypoxia. In conclusion, hypoxia triggers the activation of Notch3 which, in turn, sustains proliferation of prostate cancer cells. Notch3 pathway represents a promising target for adjuvant therapy in patients with prostate cancer.

Notch signaling molecules as prognostic biomarkers for non-small cell lung cancer

“…Moreover, univariate analysis showed that high Notch 1, Notch 3, JAG1 and DLL4 expression, TNM stage and tumor histological grading were risk factors for a poor prognosis in NSCLC patients, but multivariate analysis showed that a high level of Notch 3 expression was the only independent risk factor of prognosis for NSCLC patients, suggesting that the level of Notch 3 expression in NSCLC tissue samples may be used as a more useful prognostic marker compared with Notch 1 in NSCLC patients. Previous studies have demonstrated that cellular proliferation is significantly reduced by γ-secretase inhibitor (30,31) and that the apoptosis of Notch 3-expressing cells is induced. In lung cancer, the inhibition of Notch activation using a γ-secretase inhibitor is a potential novel approach for targeted therapy (32).…”

Notch signaling in the prostate: critical roles during development and in the hallmarks of prostate cancer biology

“…Although initially the expression of Notch3 transmembrane full-length (FL) protein in LNCaP cell was almost undetectable under hypoxia, treatment with DAPT, a γ-secretase inhibitor, increased Notch3 FL and intracellular domain expression, indicating activation of Notch3 receptor activity under low-oxygen conditions. An increase in the frequency of Notch3 immunostaining was also observed in tumor biopsies with higher Gleason score, further implicating a role for Notch3 in prostate cancer progression (Danza et al 2013).…”

“…A study reported that induction of chronic hypoxia in LNCaP human prostate cancer cells activated Notch3, but not Notch1 or Notch2, signaling to sustain cell proliferation (Danza et al 2013). Although initially the expression of Notch3 transmembrane full-length (FL) protein in LNCaP cell was almost undetectable under hypoxia, treatment with DAPT, a γ-secretase inhibitor, increased Notch3 FL and intracellular domain expression, indicating activation of Notch3 receptor activity under low-oxygen conditions.…”

Activation of Notch pathway is linked with epithelial-mesenchymal transition in prostate cancer cells

“…24 Furthermore, it has been found that Notch-3 is activated and contributes to the progression of prostate cancer. 25 High expression of Notch signaling pathway stimulated cell proliferation in prostate luminal epithelial cells. 26 Notably, Notch signaling pathway could play a role especially in the formation of PIN (prostatic intraepithelial neoplasia) structures.…”