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Published on: January 7, 2019
The NOGO receptor NgR2, a novel αVβ3 integrin effector, induces neuroendocrine differentiation in prostate cancer
Fabio Quaglia1,2, Shiv Ram Krishn1,2, Khalid Sossey-Alaoui3
1Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, PA, USA.
Abstract:
Androgen 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.
Insights
A novel pathway involving αVβ3 integrin and NgR2 promotes neuroendocrine differentiation in prostate cancer (PrCa). This discovery offers new therapeutic targets for aggressive neuroendocrine PrCa (NEPrCa), a form resistant to current treatments.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Prostate cancer (PrCa) progression to neuroendocrine PrCa (NEPrCa) presents a significant therapeutic challenge.
- Neuroendocrine PrCa (NEPrCa) is aggressive, highly metastatic, and lacks effective treatments.
- The αVβ3 integrin is upregulated during PrCa progression to NEPrCa.
Purpose of the Study:
- To elucidate a novel signaling pathway by which αVβ3 integrin promotes neuroendocrine differentiation (NED) in PrCa.
- To investigate the role of NgR2 (Nogo-66 receptor homolog 1) in αVβ3-mediated NED and NEPrCa progression.
Main Methods:
- Investigated the association between αVβ3 integrin and NgR2 in PrCa cells.
- Examined the effect of αVβ3 and NgR2 expression on neuroendocrine differentiation.
- Assessed the impact on anchorage-independent growth and cell motility.
- Detected αVβ3 and NgR2 expression in human and mouse NEPrCa samples.
Main Results:
- Identified a novel pathway where αVβ3 integrin upregulates and associates with NgR2.
- Demonstrated that NgR2 activation by αVβ3 promotes neuroendocrine differentiation (NED).
- Showed that NgR2 contributes to anchorage-independent growth and a motile phenotype in PrCa cells.
- Confirmed high expression of both αVβ3 and NgR2 in human and mouse NEPrCa.
Conclusions:
- The αVβ3-NgR2 axis represents a key pathway driving prostate cancer progression to NEPrCa.
- Targeting this pathway may offer a novel therapeutic strategy for aggressive NEPrCa.
- Further research into NgR2's role in cancer is warranted, expanding beyond its known neuronal functions.
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