Unconventional Secretion of PKCδ Exerts Tumorigenic Function via Stimulation of ERK1/2 Signaling in Liver Cancer
Unconventional Secretion of PKCδ Exerts Tumorigenic Function via Stimulation of ERK1/2 Signaling in Liver Cancer
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DOI：
10.1158/0008-5472.can-20-2009
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发表时间：
2021-01-15
期刊：
影响因子：
11.2
通讯作者：
Yoshida, Kiyotsugu
中科院分区：
文献类型：
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作者：
Yamada, Kohji;Oikawa, Tsunekazu;Yoshida, Kiyotsugu
人蛋白激酶C δ（PKC δ）蛋白的表达与许多类型的癌症有关。PKC δ是一个多功能的PKC家族成员，作为一种细胞内信号分子已被广泛研究。在这里，我们表明，PKC δ是一种分泌蛋白，调节肝癌细胞的生长。在正常细胞培养条件下的活肝癌细胞和异种移植小鼠模型中，全长PKC δ分泌到细胞外空间。肝癌患者血清PKC δ水平高于慢性肝炎、肝硬化患者和健康人。在肝癌细胞中，PKC δ以内质网（ER）-高尔基体非依赖性方式分泌，其分泌需要胞浆PKC δ的失活状态。此外，共定位研究表明，细胞外PKC δ通过与磷脂酰肌醇蛋白聚糖3（一种肝癌相关的硫酸乙酰肝素蛋白聚糖）结合锚定在肝癌细胞的细胞表面。加入外源性PKC δ激活IGF-1受体（IGF IR）的激活，随后增强ERK 1/2的激活，这导致肝癌细胞生长加速。相反，在异种移植小鼠模型中，用抗PKC δ抗体治疗减弱了IGFIR和ERK 1/2的活化，并减少了肝癌细胞的细胞增殖和球状体形成以及肿瘤生长。这项研究证明了细胞外间隙PKC delta的存在以及PKC delta作为生长因子的功能，并为肝癌的细胞外PKC delta靶向治疗提供了理论基础。意义：肝癌细胞分泌的PKC delta表现为体液生长因子，通过激活增殖信号分子促进细胞生长，这可能是潜在的诊断或治疗靶点。
Expression of human protein kinase C delta (PKC delta) protein has been linked to many types of cancers. PKC delta is known to be a multifunctional PKC family member and has been rigorously studied as an intracellular signaling molecule. Here we show that PKC delta is a secretory protein that regulates cell growth of liver cancer. Full-length PKC delta was secreted to the extracellular space in living liver cancer cells under normal cell culture conditions and in xenograft mouse models. Patients with liver cancer showed higher levels of serum PKC delta than patients with chronic hepatitis or liver cirrhosis or healthy individuals. In liver cancer cells, PKC delta secretion was executed in an endoplasmic reticulum (ER)-Golgi-independent manner, and the inactivation status of cytosolic PKC delta was required for its secretion. Furthermore, colocalization studies showed that extracellular PKC delta was anchored on the cell surface of liver cancer cells via association with glypican 3, a liver cancer-related heparan sulfate proteoglycan. Addition of exogenous PKC delta activated IGF-1 receptor (IGF IR) activation and subsequently enhanced activation of ERK1/2, which led to accelerated cell growth in liver cancer cells. Conversely, treatment with anti-PKC delta antibody attenuated activation of both IGFIR and ERK1/2 and reduced cell proliferation and spheroid formation of liver cancer cells and tumor growth in xenograft mouse models. This study demonstrates the presence of PKC delta at the extracellular space and the function of PKC delta as a growth factor and provides a rationale for the extracellular PKC delta-targeting therapy of liver cancer.Significance: PKC delta secretion from liver cancer cells behaves as a humoral growth factor that contributes to cell growth via activation of proliferative signaling molecules, which may be potential diagnostic or therapeutic targets.