Spermine synthesis inhibitor blocks 25-hydroxycholesterol-induced- apoptosis via SREBP2 upregulation in DLD-1 cell spheroids

• Published in: Biochemistry and biophysics reports Vol. 22; p. 100754
• Main Authors: Kakimoto, Miku, Yamamoto, Hideya, Tanaka, Arowu R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2020; Elsevier
• Subjects: 25-Hydroxycholesterol; APCHA; DFMO; Polyamine; SREBP2; Polyamine; INSIG; SRE; HMG-CoA; MTT; S2P; S1P; APCHA; SREBP2; poly-HEMA; SCAP; DFMO; 25-HC; 25-Hydroxycholesterol; S2P, site-2 protease; DFMO, difluoromethylornithine; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; S1P, site-1 protease; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; INSIG, insulin inducing gene; 25-HC, 25-hydroxycholesterol; SREBP2, sterol regulatory element binding protein 2; SRE, sterol response element; APCHA, N-(3-Aminopropyl)cyclohexylamine; SCAP, SREBP cleavage activating protein; poly-HEMA, poly-(2-hydroxyethyl methacrylate)
• ISSN: 2405-5808; 2405-5808
• DOI: 10.1016/j.bbrep.2020.100754

The oxysterol 25-hydroxycholesterol (25-HC) has diverse physiological activities, including the ability to inhibit anchorage-independent growth of colorectal cancer cells. Here, we found that a polyamine synthesis inhibitor, DFMO, prevented 25-HC-induced apoptosis in non-anchored colorectal cancer DLD-1 cells. Additionally, we found that the spermine synthesis inhibitor APCHA also inhibited 25-HC-induced apoptosis in DLD-1 spheroids. Inhibiting the maturation of SREBP2, a critical regulator of cholesterol synthesis, reversed the effects of APCHA. SREBP2 knockdown also abolished the ability of APCHA to counteract 25-HC activity. Furthermore, APCHA induced SREBP2 maturation and upregulated its transcriptional activity, indicating that altered polyamine metabolism can increase SREBP2 activity and block 25-HC-induced apoptosis in spheroids. These results suggest that crosstalk between polyamine metabolism and cholesterol synthetic pathways via SREBP2 governs the proliferative and malignant properties of colorectal cancer cells. •DFMO inhibits 25-HC-induced apoptosis in non-anchored DLD-1 cells.•APCHA inhibits 25-HC-induced apoptosis in DLD-1 spheroids.•APCHA induces maturation and upregulation of SREBP2.•Chemical or genetic inhibition of SREBP2 abrogates anti-apoptotic activity.