ABCA1 overexpression worsens colorectal cancer prognosis by facilitating tumour growth and caveolin‐1‐dependent invasiveness, and these effects can be ameliorated using the BET inhibitor apabetalone

Abstract

At the time of diagnosis, 20% of patients with colorectal cancer present metastasis. Among individuals with primary lesions, 50% of them will develop distant tumours with time. Therefore, early diagnosis and prediction of aggressiveness is crucial for therapy design and disease prognosis. Tumoral cells must undergo significant changes in energy metabolism to meet increased structural and energetic demands for cell proliferation, and metabolic alterations are considered to be a hallmark of cancer. Here, we present the ATP‐binding cassette transporter (ABCA1), a regulator of cholesterol transport, as a new marker for invasion and colorectal cancer survival. ABCA1 is significantly overexpressed in patients at advanced stages of colorectal cancer, and its overexpression confers proliferative advantages together with caveolin‐1 dependent‐increased migratory and invasive capacities. Thus, intracellular cholesterol imbalances mediated by ABCA1 overexpression may contribute to primary tumour growth and dissemination to distant locations. Furthermore, we demonstrate here that increased levels of apolipoprotein A1 (APOA1), a protein involved in cholesterol efflux and high‐density lipoprotein constitution, in the extracellular compartment modulates expression of ABCA1 by regulating COX‐2, and compensate for ABCA1‐dependent excessive export of cholesterol. APOA1 emerges as a new therapeutic option to inhibit the promotion of colorectal cancer to metastasis by modulating intracellular cholesterol metabolism. Furthermore, we propose apabetalone, an orally available small molecule that is currently being evaluated in clinical trials for the treatment of atherosclerosis, as a new putative therapeutic option to prevent colorectal cancer progression by increasing APOA1 expression and regulating reverse transport of cholesterol.

Non-coding RNAs in fluid shear stress-driven and reactive oxygen species-mediated colon cancer metastasis

“…Furthermore, the fact that AKT1 [74], that regulates COAD metastasis, altered in both TCGA-COAD as well as COAD-metastasis and showed association with FSS, ROS, and HCMDB-COAD is one of the most prominent results. Another noteworthy result of the OncoPrint analysis was the emergence of the transporter proteins, ABCA1 and SLC7A2 ( Figure 6a), which mediated cell invasion and tumor progression in COAD cells respectively [75,76]. Our result that SLC7A2 showed significant gene alteration in COAD but not in metastasis is supported by the literature [76].…”

Associations of cholesterol and vitamin D metabolites with the risk for development of high grade colorectal cancer

“…Apart from poor nutritional status frequently seen in CRC (20), which could be one of the reasons for decreased cho-lesterol synthesis in the liver, it has been recently proposed that reprogramming of lipid metabolism could be responsible for the observed decrease in serum lipid status markers in various types of cancer (20,21). Namely, it has been demonstrated that cancer cells extensively accumulate and use cholesterol (22,23), while such increased needs are satisfied by either upregulated endogenous synthesis (24), or enhanced uptake of circulating cholesterol (25,26). Such rearrangement of cholesterol synthesis and cellular accumulation could have important consequences regarding vitamin D status.…”

“…Although without biological activity, 25-hydroxyvitamin D (25(OH)D3) is generally accepted as a reliable marker of vitamin D status (8). However, recent evidences have emphasized 24,25-dihydroxyvitamin D (24,25 (OH) 2 D3), a catabolic product with negligible biological activity, as a promising marker for prediction of vitamin D deficiency and several associated pathological conditions (9). Accordingly, the ratio between 25(OH)D3 and 24,25(OH) 2 D3, or vitamin D metabolite ratio (VDMR) might provide more accurate insight into vitamin D status and more precise prediction of possible effects of disturbed vitamin D levels (10).…”

Alterations of Lipid Metabolism in Cancer: Implications in Prognosis and Treatment

“…The ATP-binding cassette transporter ABCA1 is a transmembrane protein responsible for the reverse cholesterol transport from the inner cell to circulatory system. ABCA1 is significantly overexpressed in patients of all stages of CRC, and its overexpression gives proliferative advantages together with caveolin-1-dependent increased migratory and invasive capacities (151). Individuals with upregulation of ABCA1 expression have an improved risk of CRC recurrence and OS independently of tumor stage (8).…”