Abstract
BackgroundColon cancer is the second leading cancer worldwide. Recurrent disease and chemotherapeutic drug resistance are very common in the advanced stage of colon cancer. ATP-citrate lyase (ACLY), the first-step rate-controlling enzyme in lipid synthesis, is elevated in colon cancer. However, it remains unclear about the exact role of ACLY in the development of colon cancer metastasis.MethodsTo evaluate the role of ACLY in colon cancer metastasis, we performed cell migration and invasion assays in two ACLY-deficient colon cancer cell lines. Colon cancer mouse model is used to examine ACLY’s effects on colon metastasis potentials in vivo. We analyzed the correlation between ACLY and CTNNB1 protein in 78 colon cancer patients by Pearson correlation. To finally explore the relationship of ACLY and CTNNB1, we used western blots, migration and invasion assays to confirm that ACLY may regulate metastasis by CTNNB1.ResultsOur data showed that the abilities of cell migration and invasion were attenuated in ACLY-deficient HCT116 and RKO cell lines. Furthermore, we describe the mechanism of ACLY in promoting colon cancer metastasis in vitro and in vivo. ACLY could stabilize CTNNB1 (beta-catenin 1) protein by interacting, and the complex might promote CTNNB1 translocation through cytoplasm to nucleus, subsequently promote the CTNNB1 transcriptional activity and migration and invasion abilities of colon cancer cells. Immunohistochemical analysis of 78 colon cancer patients showed that the high expression levels of ACLY and CTNNB1 protein was positively correlated with metastasis of colon cancer.ConclusionsThese results shed new light on the molecular mechanism underlying colon cancer metastasis, which might help in improving therapeutic efficacy.
Highlights
Colon cancer is the second leading cancer worldwide
We identified that ATP-citrate lyase (ACLY) stabilized CTNNB1 protein by interacting, and the complex might promote CTNNB1 translocation through cytoplasm to nucleus, which promoted the CTNNB1 transcriptional activity and migration and invasion abilities of colon cancer cells
Our data shed new light on the molecular mechanism underlying colon cancer metastasis, which might help in improving therapeutic efficacy
Summary
Recurrent disease and chemotherapeutic drug resistance are very common in the advanced stage of colon cancer. ATP-citrate lyase (ACLY), the first-step ratecontrolling enzyme in lipid synthesis, is elevated in colon cancer. It remains unclear about the exact role of ACLY in the development of colon cancer metastasis. Tumor cells in colonization adjust themselves to adapt to the new microenvironment and switch from migration mode to proliferation mode in order to form metastases [7]. Metabolism reprogramming provides sufficient energy, amino acids, ribose, phospholipids and other macromolecules to meet demands for rapid proliferation [8], and it might play a critical role during the process of tumor metastasis
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