Increased phosphorylation of AMPKα1 S485 in colorectal cancer and identification of PKCα as a responsible kinase

IF 9.1 1区 医学 Q1 ONCOLOGY
Yan Zhou , Tingting Lei , Zhimin Tang , Pei Guo , Deqiang Huang , Zhijun Luo , Linyu Luo
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Abstract

The present study attempts to examine the biological effect of phosphorylation of AMPKα1 S485 and identify the responsible kinase in colon cancer cells. Thus, our results showed that S485 phosphorylation was increased in colorectal cancer specimens as compared with adjacent normal tissues, which was inversely correlated to phosphorylation of T172. Our study further revealed that phosphorylation of S485 on AMPKα1 plays a promoting role in cell proliferation, colony formation, migration and growth of Xenograft tumor. Furthermore, we identified PKCα as a kinase specific for phosphorylation of S485. First, under the basal condition, S485 phosphorylation was blunted by Gö6983, a pan PKC inhibitor, but not by Akt inhibitor, MK2206, although the latter countered off the insulin-stimulated phosphorylation. Second, the phosphorylation was enhanced by PMA and attenuated by sgRNA for PKCα, but not by PKCγ and PKCδ, neither by siRNA for Akt1. Third, the phosphorylation was suppressed by shRNA for PLCγ1. Fourth, the phosphorylation was enhanced by ectopically expressing a constitutively active mutant of PKCα, but not PKCγ. Finally, the increase of S485 phosphorylation by high glucose or palmitic acid was almost completely abolished by Gö6983. Altogether, our data reinforced the tumor suppressive function of AMPK and demonstrated that PKCα is a major kinase responsible for phosphorylation of S485, which contributes to one of the mechanisms underlying the regulation of AMPK in cancer cells in response to nutritional conditions.
结直肠癌中AMPKα1 S485磷酸化的增加和PKCα作为负责任激酶的鉴定。
本研究旨在探讨结肠癌细胞AMPKα1 S485磷酸化的生物学效应,并鉴定其相关激酶。因此,我们的研究结果表明,与邻近正常组织相比,结直肠癌标本中S485的磷酸化水平升高,这与T172的磷酸化水平呈负相关。我们的研究进一步揭示了S485对AMPKα1的磷酸化在异种移植瘤的细胞增殖、集落形成、迁移和生长中起促进作用。此外,我们发现PKCα是S485磷酸化的特异性激酶。首先,在基础条件下,S485的磷酸化被PKC抑制剂Gö6983钝化,而Akt抑制剂MK2206没有钝化,尽管后者抵消了胰岛素刺激的磷酸化。其次,PMA对PKCα的磷酸化增强,sgRNA对PKCα的磷酸化减弱,但PKCγ和PKCδ没有磷酸化,而siRNA对Akt1也没有磷酸化。第三,plc - γ - 1的磷酸化被shRNA抑制。第四,磷酸化通过异位表达PKCα而非PKCγ的组成型活性突变体而增强。最后,通过Gö6983几乎完全消除了高糖或棕榈酸对S485磷酸化的增加。总之,我们的数据加强了AMPK的肿瘤抑制功能,并证明PKCα是负责S485磷酸化的主要激酶,这有助于癌细胞对营养条件的调节AMPK的机制之一。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
期刊介绍: Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.
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