Curcumin suppresses cell proliferation and reduces cholesterol absorption in Caco-2 cells by activating the TRPA1 channel

Abstract

Background Curcumin (Cur) is a bioactive dietary polyphenol of turmeric with various biological activities against several cancers. Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths. Intestinal cholesterol homeostasis is associated with CRC. Chemotherapy for CRC is related to varied adverse effects. Therefore, natural products with anti-cancer properties represent a potential strategy for primary prevention of CRC. Methods The present study used Cur as a therapeutic approach against CRC using the Caco-2 cell line. The cells were treated with different concentrations of Cur for different duration of time and then the proliferation ability of cells was assessed using Cell Counting Kit-8 and 5-Ethynyl-2′-deoxyuridine assays. Oil red O staining and cholesterol assay kit were used to evaluate cellular lipid content and cholesterol outward transportation. Finally, the protein expressions of cholesterol transport-related protein and signal transduction molecules were assessed using Western blot assay. Results Cur inhibited cell proliferation in Caco-2 cells in a dose- and time-dependent manner by activating the transient receptor potential cation channel subfamily A member 1 (TRPA1) channel. Activation of the TRPA1 channel led to increased intracellular calcium, peroxisome proliferator-activated receptor gamma (PPARγ) upregulation, and the subsequent downregulation of the specificity protein-1 (SP-1)/sterol regulatory element-binding protein-2 (SREBP-2)/Niemann-Pick C1-like 1 (NPC1L1) signaling pathway-related proteins, and finally reduced cholesterol absorption in Caco-2 cells. Conclusions Cur inhibits cell proliferation and reduces cholesterol absorption in Caco-2 cells through the Ca2+/PPARγ/SP-1/SREBP-2/NPC1L1 signaling by activating the TRPA1 channel, suggesting that Cur can be used as a dietary supplement for the primary prevention of CRC. Graphical Abstract In Caco-2 cells, Cur first stimulates calcium influx by activating the TRPA1 channel, further upregulates PPARγ and downregulates SP-1/SREBP-2/NPC1L1 signaling pathway, and finally inhibits the absorption of cholesterol. TRPA1, transient receptor potential cation channel subfamily A member 1; NPC1L1, Niemann-Pick C1-like 1; PPARγ, peroxisome proliferator-activated receptor gamma; SP-1, specificity protein-1; SREBP-2, sterol regulatory element-binding protein-2; Cur, curcumin.

Cholesterol in colorectal cancer: an essential but tumorigenic precursor?

“…Moreover, it has been shown that curcumin via the Ca 2+ /PPARg/ SP-1/SREBP-2/NPC1L1 signaling and also through stimulating the transient receptor potential ankyrin 1 (TRPA1) can suppress tumor cell proliferation and reduce cholesterol absorption in Caco-2 cells. These data indicate that curcumin as a dietary supplement may benefit primary CRC prevention (137).…”

Curcumin-Based Fixed Dose Combination Products for Cholesterol Management: A Narrative Review

“…Curcumin may overwhelm cell proliferation and lessen cholesterol absorption in Caco-2 cells by activating the TRPA1 channel …”

“…Curcumin may overwhelm cell proliferation and lessen cholesterol absorption in Caco-2 cells by activating the TRPA1 channel. 52 Based on a hamster animal model, curcumin may defend against high-fat-diet-induced nonalcoholic simple fatty liver by preventing intestinal and hepatic NPC1L1 expression via downregulation of the SREBP-2/HNF1α pathway. 53 Finally, curcumin has antioxidant effects.…”

Targeting dysregulated lipid metabolism in the tumor microenvironment

“…Curcumin functions in the lipid metabolism of various types of cancers, inducing apoptosis in human breast cancer MDA-MB-231 and liver cancer HepG2 cell lines, which is mediated by the downregulation of FASN (Fan et al 2014 , 2016 ). In addition to its inhibitory effect on lipogenesis, curcumin decreased cholesterol absorption into human colorectal cancer Caco-2 cells, suppressing cancer cell proliferation (Qin et al 2023 ). Moreover, curcumin attenuated stem cell phenotypes of human breast cancer cells through the downregulation of fatty acid desaturases, such as SCD, FADS1, and FASD2 (Colacino et al 2016 ).…”