Notch3 is activated by chronic hypoxia and contributes to the progression of human prostate cancer.
Notch3 is activated by chronic hypoxia and contributes to the progression of human prostate cancer.
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DOI：
10.1002/ijc.28293
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发表时间：
2013-12-01
影响因子：
6.4
通讯作者：
Tarantini, Francesca
中科院分区：
文献类型：
--
作者：
Danza, Giovanna;Di Serio, Claudia;Ambrosio, Maria Raffaella;Sturli, Niccolo;Lonetto, Giuseppe;Rosati, Fabiana;Rocca, Bruno Jim;Ventimiglia, Giuseppina;del Vecchio, Maria Teresa;Prudovsky, Igor;Marchionni, Niccolo;Tarantini, Francesca
前列腺癌仍然是男性癌症相关死亡的第二大原因。尽管有转移症状的患者有不祥的结局，但绝大多数PC在早期阶段就被诊断出来了。尽管如此，即使是在临床局限性疾病的患者中，结果也可能有很大的不同。除了雄激素敏感性，人们对侵袭性、局限性癌症中还有哪些信号通路发生了错乱知之甚少。对这些途径的阐明可能有助于开发针对特定分子靶点的创新疗法。我们报道了在激素敏感的前列腺癌LNCaP细胞系中，Notch3在低氧条件下被激活，并在软琼脂中持续细胞增殖和克隆形成。低氧还调节细胞胆固醇含量和脂筏的数量和大小，导致小筏合并成更大的簇；在本实验条件下，Notch3从非筏迁移到筏隔间，在那里它与γ分泌酶复合体共同定位。我们还观察了人类前列腺癌活检组织，发现Notch3的表达与Gleason评分和碳酸氢酶IX的表达呈正相关，碳酸酐酶IX是缺氧的标志。总而言之，低氧触发了Notch3的激活，而Notch3反过来又支持前列腺癌细胞的增殖。NOTCH3通路有望成为前列腺癌患者辅助治疗的靶点。
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.
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影响因子：
5.3
作者：
Cecchi C;Rosati F;Pensalfini A;Formigli L;Nosi D;Liguri G;Dichiara F;Morello M;Danza G;Pieraccini G;Peri A;Serio M;Stefani M
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通讯作者：
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5.3
作者：
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通讯作者：
Weinmaster, Gerry