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CRKL 通过激活 PI3K/Akt 促进肝癌细胞的葡萄糖代谢。

CRKL promotes hepatocarcinoma through enhancing glucose metabolism of cancer cells via activating PI3K/Akt.

机构信息

Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China.

Carlson School of Chemistry and Biochemistry, Clark University, Worcester, MA, USA.

出版信息

J Cell Mol Med. 2021 Mar;25(5):2714-2724. doi: 10.1111/jcmm.16303. Epub 2021 Feb 1.

DOI:10.1111/jcmm.16303
PMID:33523562
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7933966/
Abstract

Abnormal glucose metabolism may contribute to cancer progression. As a member of the CRK (v-crk sarcoma virus CT10 oncogene homologue) adapter protein family, CRKL (CRK-like) associated with the development and progression of various tumours. However, the exact role and underlying mechanism of CRKL on energy metabolism remain unknown. In this study, we investigated the effect of CRKL on glucose metabolism of hepatocarcinoma cells. CRKL and PI3K were found to be overexpressed in both hepatocarcinoma cells and tissues; meanwhile, CRKL up-regulation was positively correlated with PI3K up-regulation. Functional investigations revealed that CRKL overexpression promoted glucose uptake, lactate production and glycogen synthesis of hepatocarcinoma cells by up-regulating glucose transporters 1 (GLUT1), hexokinase II (HKII) expression and down-regulating glycogen synthase kinase 3β (GSK3β) expression. Mechanistically, CRKL promoted glucose metabolism of hepatocarcinoma cells via enhancing the CRKL-PI3K/Akt-GLUT1/HKII-glucose uptake, CRKL-PI3K/Akt-HKII-glucose-lactate production and CRKL-PI3K/Akt-Gsk3β-glycogen synthesis. We demonstrate CRKL facilitates HCC malignancy via enhancing glucose uptake, lactate production and glycogen synthesis through PI3K/Akt pathway. It provides interesting fundamental clues to CRKL-related carcinogenesis through glucose metabolism and offers novel therapeutic strategies for hepatocarcinoma.

摘要

异常的葡萄糖代谢可能促进癌症的进展。作为 CRK（v-crk 肉瘤病毒 CT10 癌基因同源物）衔接蛋白家族的一员，CRKL（CRK 样）与各种肿瘤的发生和发展有关。然而，CRKL 对能量代谢的确切作用和潜在机制尚不清楚。在这项研究中，我们研究了 CRKL 对肝癌细胞葡萄糖代谢的影响。发现 CRKL 和 PI3K 在肝癌细胞和组织中均过度表达；同时，CRKL 的上调与 PI3K 的上调呈正相关。功能研究表明，CRKL 的过表达通过上调葡萄糖转运蛋白 1（GLUT1）、己糖激酶 II（HKII）的表达和下调糖原合酶激酶 3β（GSK3β）的表达，促进肝癌细胞的葡萄糖摄取、乳酸生成和糖原合成。在机制上，CRKL 通过增强 CRKL-PI3K/Akt-GLUT1/HKII-葡萄糖摄取、CRKL-PI3K/Akt-HKII-葡萄糖-乳酸生成和 CRKL-PI3K/Akt-Gsk3β-糖原合成来促进肝癌细胞的葡萄糖代谢。我们证明，CRKL 通过 PI3K/Akt 通路增强葡萄糖摄取、乳酸生成和糖原合成，促进 HCC 恶性肿瘤的发生。这为通过葡萄糖代谢研究 CRKL 相关致癌作用提供了有趣的基础线索，并为肝癌提供了新的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b95/7933966/0c2f4e9c05e3/JCMM-25-2714-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b95/7933966/fc3ae027ed98/JCMM-25-2714-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b95/7933966/de4c3ae8a376/JCMM-25-2714-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b95/7933966/26e56f2ef76d/JCMM-25-2714-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b95/7933966/ae20cad5e9c6/JCMM-25-2714-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b95/7933966/6cf955b4124b/JCMM-25-2714-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b95/7933966/0c2f4e9c05e3/JCMM-25-2714-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b95/7933966/fc3ae027ed98/JCMM-25-2714-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b95/7933966/de4c3ae8a376/JCMM-25-2714-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b95/7933966/26e56f2ef76d/JCMM-25-2714-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b95/7933966/ae20cad5e9c6/JCMM-25-2714-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b95/7933966/6cf955b4124b/JCMM-25-2714-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b95/7933966/0c2f4e9c05e3/JCMM-25-2714-g006.jpg

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