INSERM, U976, Centre de Recherche sur la Peau, F-75010 Paris, France.
Univ Paris Diderot, Sorbonne Paris Cité, UMR 976, F-75010 Paris, France.
Oncogene. 2017 Jun 8;36(23):3252-3262. doi: 10.1038/onc.2016.469. Epub 2017 Jan 16.
The cyclic AMP (cAMP) signaling pathway is critical in melanocyte biology for regulating differentiation. It is downregulated by phosphodiesterase (PDE) enzymes, which degrade cAMP itself. In melanoma evidence suggests that inhibition of the cAMP pathway by PDE type 4 (PDE4) favors tumor progression. For example, in melanomas harboring RAS mutations, the overexpression of PDE4 is crucial for MAPK pathway activation and proliferation induced by oncogenic RAS. Here we showed that PDE4D is overexpressed in BRAF-mutated melanoma cell lines, constitutively disrupting the cAMP pathway activation. PDE4D promoted melanoma invasion by interacting with focal adhesion kinase (FAK) through the scaffolding protein RACK1. Inhibition of PDE4 activity or inhibition of PDE4D interaction with FAK reduced invasion. PDE4D expression is increased in patients with advanced melanoma and PDE4D-FAK interaction is detectable in situ in metastatic melanoma. Our study establishes the role of PDE4D in BRAF-mutated melanoma as regulator of cell invasion, and suggests its potential as a target for preventing metastatic dissemination.
环腺苷酸 (cAMP) 信号通路在黑素细胞生物学中对于调节分化至关重要。它被磷酸二酯酶 (PDE) 酶下调，这些酶本身降解 cAMP。在黑色素瘤中，有证据表明 PDE4 型（PDE4）抑制 cAMP 通路有利于肿瘤进展。例如，在携带 RAS 突变的黑色素瘤中，PDE4 的过度表达对于由致癌性 RAS 诱导的 MAPK 通路激活和增殖至关重要。在这里，我们表明 PDE4D 在 BRAF 突变的黑色素瘤细胞系中过表达，持续破坏 cAMP 通路的激活。PDE4D 通过支架蛋白 RACK1 与粘着斑激酶 (FAK) 相互作用促进黑色素瘤侵袭。抑制 PDE4 活性或抑制 PDE4D 与 FAK 的相互作用可降低侵袭性。晚期黑色素瘤患者中 PDE4D 的表达增加，并且在转移性黑色素瘤中可在原位检测到 PDE4D-FAK 相互作用。我们的研究确立了 PDE4D 在 BRAF 突变的黑色素瘤中的作用作为细胞侵袭的调节剂，并表明其作为预防转移扩散的潜在靶点。
