Abstract
SCP1 as a nuclear transcriptional regulator acts globally to silence neuronal genes and to affect the dephosphorylation of RNA Pol ll. However, we report the first finding and description of SCP1 as a plasma membrane-localized protein in various cancer cells using EGFP- or other epitope-fused SCP1. Membrane-located SCP1 dephosphorylates AKT at serine 473, leading to the abolishment of serine 473 phosphorylation that results in suppressed angiogenesis and a decreased risk of tumorigenesis. Consistently, we observed increased AKT phosphorylation and angiogenesis followed by enhanced tumorigenesis in Ctdsp1 (which encodes SCP1) gene - knockout mice. Importantly, we discovered that the membrane localization of SCP1 is crucial for impeding angiogenesis and tumor growth, and this localization depends on palmitoylation of a conserved cysteine motif within its NH2 terminus. Thus, our study discovers a novel mechanism underlying SCP1 shuttling between the plasma membrane and nucleus, which constitutes a unique pathway in transducing AKT signaling that is closely linked to angiogenesis and tumorigenesis.
Highlights
Tumor angiogenesis is required for tumor growth and metastasis since tumors cannot grow without nutrients and oxygen when their diameters are beyond 1–2 mm, which is considered a distinct characteristic of cancer progression from early to terminal stages (Folkman, 1971; Nicholson and Theodorescu, 2004)
To explore the functional role of SCP1 in the inhibition of AKT activity, we surprisingly found that both GFP-SCP1 and Flag-SCP1 were mainly localized at the plasma membrane in HeLa cells, where they were well co-localized with the plasma membrane marker GFP-PLCd-PH (Figure 1A)
Because angiogenesis is essential for tumorigenesis (Testa and Bellacosa, 2001), we explored the role of SCP1 on tumor growth by injecting Lewis lung carcinoma cells (LLCs) into WT or SCP1-KO mice (O’Reilly et al, 1994)
Summary
Tumor angiogenesis is required for tumor growth and metastasis since tumors cannot grow without nutrients and oxygen when their diameters are beyond 1–2 mm, which is considered a distinct characteristic of cancer progression from early to terminal stages (Folkman, 1971; Nicholson and Theodorescu, 2004). Angiogenesis inhibition approaches have emerged as attractive and promising strategies in anti-cancer treatment. AKT is a central protein kinase in various cell activities, especially for angiogenesis, tumor growth, and progression (Vivanco and Sawyers, 2002; Manning and Cantley, 2007). Therapeutic strategies targeting the inhibition of AKT activity in cancer treatments have drawn great public attention during recent decades. AKT is activated by different extracellular signals such as GPCRs (G protein-coupled receptor), growth factors, and integrins (Hemmings and Restuccia, 2015, 2012).
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