磷脂翻转酶 1 的 N 端结构域抗体阻断可减少结直肠癌细胞的体外和体内致瘤性。

BACKGROUND

Membrane-bound phospholipid scramblase 1 (PLSCR1) is involved in both lipid trafficking and cell signaling. Previously, we showed that PLSCR1 is overexpressed in many colorectal carcinomas (CRCs). In the present study, we investigated the tumorigenic role of PLSCR1 in CRC and suggest that it is a potential therapeutic target.

METHODS

To identify PLSCR1 as a therapeutic target, we studied the tumorigenic properties of CRC cell lines treated with a monoclonal antibody (NP1) against the N-terminus of PLSCR1 in vitro and in vivo. We also investigated cell cycle status and epidermal growth factor receptor-related pathways and downstream effectors of PLSCR1 after blocking its function with NP1.

RESULTS

Treating CRC cells with NP1 in vitro and in vivo decreased cell proliferation, anchorage-independent growth, migration, and invasion. Adding NP1 to the CRC cell line HT29 caused arrest at G1/S. Treating HT29 cells with NP1 significantly decreased the expression of cyclin D1 and phosphorylation levels of Src, the adaptor protein Shc, and Erks. The reduced level of cyclin D1 led to an increase in the activated form of the tumor suppressor retinoblastoma protein via dephosphorylation. These actions led to attenuation of tumorigenesis.

CONCLUSIONS

Therefore, PLSCR1 may serve as a potential therapeutic target for CRC.

背景

膜结合磷脂翻转酶 1（PLSCR1）参与脂质运输和细胞信号转导。先前，我们发现 PLSCR1 在许多结直肠癌（CRC）中过度表达。在本研究中，我们研究了 PLSCR1 在 CRC 中的致瘤作用，并表明它是一个潜在的治疗靶点。

方法

为了确定 PLSCR1 作为治疗靶点，我们研究了针对 PLSCR1 N 端的单克隆抗体（NP1）在体外和体内处理 CRC 细胞系的致瘤特性。我们还研究了阻断其功能后 NP1 对细胞周期状态和表皮生长因子受体相关途径以及 PLSCR1 的下游效应物的影响。

结果

体外和体内用 NP1 处理 CRC 细胞可降低细胞增殖、锚定非依赖性生长、迁移和侵袭。将 NP1 添加到 CRC 细胞系 HT29 中可导致 G1/S 期阻滞。用 NP1 处理 HT29 细胞可显著降低 cyclin D1 的表达和 Src、衔接蛋白 Shc 和 Erks 的磷酸化水平。cyclin D1 水平的降低导致肿瘤抑制蛋白视网膜母细胞瘤蛋白的激活形式通过去磷酸化增加。这些作用导致肿瘤发生减弱。