Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Departments of Medicine and Microbiology & Immunology, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Sci Transl Med. 2020 Jan 22;12(527). doi: 10.1126/scitranslmed.aax3772.
Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIβ (PI4KIIIβ). Molecular, biochemical, and cell biological studies show that PI4KIIIβ-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating Golgi phosphoprotein 3 (GOLPH3)-dependent vesicular release from the Golgi. PI4KIIIβ-dependent secreted factors maintain 1q-amplified cancer cell survival and influence prometastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIIIβ antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a dependency on PI4KIIIβ-dependent secretion for cancer cell survival and tumor progression.
促肿瘤效应蛋白的分泌增加是恶性细胞的一个特征。然而，这一特征的分子基础和治疗意义仍不清楚。在这里，我们确定了一个经常在多种癌症类型中扩增的染色体 1q 区域，该区域编码多个调节分泌囊泡生物发生和运输的调节剂，包括高尔基定向酶磷脂酰肌醇（PI）-4-激酶 IIIβ（PI4KIIIβ）。分子、生化和细胞生物学研究表明，PI4KIIIβ 衍生的 PI-4-磷酸（PI4P）合成通过激活高尔基磷蛋白 3（GOLPH3）依赖性囊泡从高尔基释放，增强分泌并加速肺腺癌的进展。PI4KIIIβ 依赖性分泌因子维持 1q 扩增癌细胞的存活，并影响肿瘤微环境中的促转移过程。用选择性 PI4KIIIβ 拮抗剂破坏 1q 扩增癌细胞中的这种功能电路，可诱导细胞凋亡并抑制肿瘤生长和转移。这些结果支持这样一种模型，即染色体 1q 扩增为癌细胞的存活和肿瘤的进展创造了对 PI4KIIIβ 依赖性分泌的依赖性。
