Abstract
Currently, no frontline treatment is effective for the late-stage colorectal cancer (CRC). Understanding the molecular differences in different stages of CRC can help us to identify the critical therapeutic targets for designing therapeutic strategy. Our data show that c-Myc protein is highly expressed in late-stage CRC when compared with early-stage CRC in both clinical samples and in cell lines representing different cancer stages. Given that c-Myc is a well-known oncogenic driver in CRC, its high expression in the late-stage CRC may represent a critical therapeutic target for treating the cancer. Dihydroartemisinin treatment significantly increases c-Myc protein degradation and hence reduces its expression in CRC. The treatment also reduces CRC cell viability. Interestingly, dihydroartemisinin exhibits a more potent growth-inhibitory effect in late-stage CRC than the early-stage CRC. The treatment also possesses potent growth-inhibitory effects in mouse models bearing c-Myc-overexpressed CRC. The reduced c-Myc level and its reduced transcriptional activity reduce the expressions of acetyl-CoA carboxylase, fatty acid synthase, carnitine–palmitoyltransferase-1, and medium-chain acyl-CoA dehydrogenase in the cancer cells. Lipidomics study also shows that dihydroartemisinin treatment changes the metabolic phenotypes in CRC, reduces oxygen consumption, respiration, and ATP production, hence reduces the cell proliferation and induces apoptosis. Our study provides strong pharmacological evidence to support the translation of dihydroartemisinin for the treatment of late-stage CRC by targeting c-Myc.
Highlights
Colorectal cancer (CRC) is one of the most common cancers worldwide
Our study clearly shows that c-Myc expression is higher in CRC than in normal colon epithelial cells, the expression of c-Myc in CRC is directly correlated with the staging of the cancer
Dihydroartemisinin treatment significantly reduces the expressions of c-Myc and its downstream targets acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), carnitine palmitoyltransferase-1 (CPT-1), and medium-chain acyl-CoA dehydrogenase (MCAD), which changes the lipid metabolism and the metabolic phenotypes in CRC, reduces energy production, cell proliferation, and induces cancer-cell death
Summary
Colorectal cancer (CRC) is one of the most common cancers worldwide. It is estimated that there will be 147,950 new CRC cases with 53,200 deaths in year 2020 [1]. No frontline treatment is effective for the late-stage CRC, which results in high mortality. Studies show that c-Myc expressions in CRC are elevated in 32–72% of the clinical cases [3,4,5,6,7]. These aberrant expressions of Myc are induced by the constitutive activation of mutated Ras [8], or via chromosomal translocation, gene amplification, and posttranslational modifications. Since c-Myc regulates the transcription of the genes that are involved in cell proliferation, cell cycle, protein synthesis, cell migration, and adhesion [1, 2, 9, 10], its elevation drives the cancer to grow
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