AKR1B10 activates diacylglycerol (DAG) second messenger in breast cancer cells
Autor: | Junfei Jin, Dan Huang, Deliang Cao, Duan-Fang Liao, Chenfei Huang, Guiyuan Shi, Haitao Ji, Yi Shen, Yiwen Bu, Jun Ma, Zhe Cao, Ramina Khoshaba |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
MAPK/ERK pathway Cancer Research MAP Kinase Signaling System Transplantation Heterologous Mice Nude Breast Neoplasms Biology Second Messenger Systems Article Metastasis Diglycerides 03 medical and health sciences Cyclin D1 Breast cancer Cell Line Tumor medicine Animals Humans Molecular Biology Protein Kinase C Protein kinase C Diacylglycerol kinase Aldo-Keto Reductase Family 1 member B10 Cell growth Lipogenesis medicine.disease Tumor Burden HEK293 Cells 030104 developmental biology Second messenger system MCF-7 Cells Cancer research Female |
Zdroj: | Molecular Carcinogenesis. 57:1300-1310 |
ISSN: | 0899-1987 |
Popis: | Aldo-keto reductase 1B10 (AKR1B10) is upregulated in breast cancer and promotes tumor growth and metastasis. However, little is known of the molecular mechanisms of action. Herein we report that AKR1B10 activates lipid second messengers to stimulate cell proliferation. Our data showed that ectopic expression of AKR1B10 in breast cancer cells MCF-7 promoted lipogenesis and enhanced levels of lipid second messengers, including phosphatidylinositol bisphosphate (PIP2), diacylglycerol (DAG), and inositol triphosphate (IP3). In contrast, silencing of AKR1B10 in breast cancer cells BT-20 and colon cancer cells HCT-8 led to decrease of these lipid messengers. Qualitative analyses by liquid chromatography-mass spectrum (LC-MS) revealed that AKR1B10 regulated the cellular levels of total DAG and majority of subspecies. This in turn modulated the phosphorylation of protein kinase C (PKC) isoforms PKCδ (Thr505), PKCµ (Ser744/748), and PKCα/βII (Thr638/641) and activity of the PKC-mediated c-Raf/MEK/ERK signaling cascade. A pan inhibitor of PKC (Go6983) blocked ERK1/2 activation by AKR1B10. In these cells, phospho-p90RSK, phospho-MSK, and Cyclin D1 expression was increased by AKR1B10, and pharmacological inhibition of the ERK signaling cascade with MEK1/2 inhibitors U0126 and PD98059 eradicated induction of phospho-p90RSK, phospho-MSK, and Cyclin D1. In breast cancer cells, AKR1B10 promoted the clonogenic growth and proliferation of breast cancer cells in two-dimension (2D) and three-dimension (3D) cultures and tumor growth in immunodeficient female nude mice through activation of the PKC/ERK pathway. These data suggest that AKR1B10 stimulates breast cancer cell growth and proliferation through activation of DAG-mediated PKC/ERK signaling pathway. |
Databáze: | OpenAIRE |
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