AIBP and APOA-I synergistically inhibit intestinal tumor growth and metastasis by promoting cholesterol efflux

Tao Zhang; Qilong Wang; Yeqi Wang; Junping Wang; Yongping Su; Fengchao Wang; Guixue Wang

doi:10.1186/s12967-019-1910-7

AIBP and APOA-I synergistically inhibit intestinal tumor growth and metastasis by promoting cholesterol efflux

J Transl Med. 2019 May 17;17(1):161. doi: 10.1186/s12967-019-1910-7.

Authors

Tao Zhang^{1

2}, Qilong Wang¹, Yeqi Wang¹, Junping Wang², Yongping Su², Fengchao Wang³, Guixue Wang⁴

Affiliations

¹ Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, China.
² Institute of Combined Injury, State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University, Chongqing, China.
³ Institute of Combined Injury, State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University, Chongqing, China. Wfch@tmmu.edu.cn.
⁴ Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, China. wanggx@cqu.edu.cn.

Abstract

Background: The roles played by cholesterol in cancer development and progression represent a popular field in the cancer community. High cholesterol levels are positively correlated with the risk of various types of cancer. APOA-I binding protein (AIBP) promotes the reverse cholesterol transport pathway (RCT) in cooperation with Apolipoprotein A-I (APOA-I) or high-density lipoprotein cholesterol. However, the combined effect of AIBP and APOA-I on intestinal tumor cells is still unclear.

Methods: Immunohistochemistry, western blot and qPCR were performed to investigate the expression of AIBP and APOA-I in intestinal tumor tissues and cell lines. The anti-tumor activity of AIBP and APOA-I was evaluated by overexpression or recombinant protein treatment. Cholesterol efflux and localization of lipid raft-related proteins were analyzed by a cholesterol efflux assay and lipid raft fraction assay, respectively.

Results: Here, we reported that both AIBP expression and APOA-I expression were associated with the degree of malignancy in intestinal tumors. Co-overexpression of AIBP and APOA-I more potently inhibited colon cancer cell-mediated tumor growth and metastasis compared to overexpression of each protein individually. Additionally, the recombinant fusion proteins of AIBP and APOA-I exhibited a significant therapeutic effect on tumor growth in Apc^min/+ mice as an inherited intestinal tumor model. The synergistic effect of the two proteins inhibited colon cancer cell migration, invasion and tumor-induced angiogenesis by promoting cholesterol efflux, reducing the membrane raft content, and eventually disrupting the proper localization of migration- and invasion-related proteins on the membrane raft. Moreover, cyclosporine A, a cholesterol efflux inhibitor, rescued the inhibitory effect induced by the combination of AIBP and APOA-I.

Conclusions: These results indicate that the combination of APOA-I and AIBP has an obvious anticancer effect on colorectal cancer by promoting cholesterol efflux.

Keywords: AIBP; APOA-I; Cholesterol efflux; Colorectal cancer; RCT.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apolipoprotein A-I / metabolism*
Biological Transport
Cell Line
Cell Movement
Cell Proliferation
Cholesterol / metabolism*
Humans
Intestinal Neoplasms / metabolism*
Intestinal Neoplasms / pathology*
Mice, Inbred C57BL
Neoplasm Invasiveness
Neoplasm Metastasis
Neovascularization, Pathologic / metabolism
Neovascularization, Pathologic / pathology
Phosphoproteins / metabolism*
Racemases and Epimerases / metabolism*

Substances

Apolipoprotein A-I
Phosphoproteins
Cholesterol
Naxe protein, mouse
Racemases and Epimerases