Author:
Quaglia Fabio,Krishn Shiv Ram,Sossey-Alaoui Khalid,Rana Priyanka Shailendra,Pluskota Elzbieta,Park Pyung Hun,Shields Christopher D.,Lin Stephen,McCue Peter,Kossenkov Andrew V.,Wang Yanqing,Goodrich David W.,Ku Sheng-Yu,Beltran Himisha,Kelly William K.,Corey Eva,Klose Maja,Bandtlow Christine,Liu Qin,Altieri Dario C.,Plow Edward F.,Languino Lucia R.
Abstract
AbstractAndrogen deprivation therapies aimed to target prostate cancer (PrCa) are only partially successful given the occurrence of neuroendocrine PrCa (NEPrCa), a highly aggressive and highly metastatic form of PrCa, for which there is no effective therapeutic approach. Our group has demonstrated that while absent in prostate adenocarcinoma, the αVβ3 integrin expression is increased during PrCa progression toward NEPrCa. Here, we show a novel pathway activated by αVβ3 that promotes NE differentiation (NED). This novel pathway requires the expression of a GPI-linked surface molecule, NgR2, also known as Nogo-66 receptor homolog 1. We show here that NgR2 is upregulated by αVβ3, to which it associates; we also show that it promotes NED and anchorage-independent growth, as well as a motile phenotype of PrCa cells. Given our observations that high levels of αVβ3 and, as shown here, of NgR2 are detected in human and mouse NEPrCa, our findings appear to be highly relevant to this aggressive and metastatic subtype of PrCa. This study is novel because NgR2 role has only minimally been investigated in cancer and has instead predominantly been analyzed in neurons. These data thus pave new avenues toward a comprehensive mechanistic understanding of integrin-directed signaling during PrCa progression toward a NE phenotype.
Publisher
Springer Science and Business Media LLC
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