Bromelain effectively suppresses Kras-mutant colorectal cancer by stimulating ferroptosis

Abstract

Here, we investigated the possible anti-cancer properties of bromelain in Kras mutant human colorectal carcinoma cell lines and a mouse model harboring a Kras mutation. Cell growth and proliferation were significantly reduced in the Kras mutant colorectal carcinoma cell lines following treatment with 50 μg/mL bromelain as assessed by crystal violet staining and a proliferation assay. To identify the molecules responsible for this action, the expression levels of genes involved in signaling pathways and miRNAs were analyzed by real-time PCR. Among the genes tested, down-regulation of ACSL-4 and up-regulation of miRNAs targeting ASCL-4 were observed in Caco2 cells. Compared to the Kras wild-type colorectal carcinoma cell lines, Kras mutant colorectal carcinoma cell lines exhibited a remarkably up-regulated expression of ACSL-4, which is responsible for ferroptosis sensitivity. Moreover, the knockdown of ACSL-4 by a specific shRNA inhibited erastin-induced ferroptosis in Kras mutant DLD-1 cells as assessed by propidium iodide staining and lipid reactive oxygen species measurement. Our findings indicate that bromelain effectively exerts cytotoxic effects in Kras mutant colorectal cancer cells compared to in Kras wild-type colorectal cancer cells. Differential expression of ACSL-4 is responsible for the differential action of bromelain in regulating ferroptotic cell death.

Ferroptosis, a new form of cell death: opportunities and challenges in cancer

“…Besides the clinically approved drugs, two antibiotics such as salinomycin and ironomycin can promote ferroptosis in colon cancer cells via interfering with iron metabolism allowing for ROS production [65]. Other natural compounds such as bromelain [50], baicalein, artenimol, artemisinin, cotylenin A (CN-A) [11], and various vitamins can regulate cell ferroptotic death by acting on the lipid peroxidation and ROS occurrence (Table 3). Numerous nanomaterials have also been prospered for ferroptosis-based cancer therapy.…”

“…Beyond that, previous studies have confirmed that ROS generation requires the activation of polyunsaturated fatty acids (PUFAs) by Acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3). MiR-3595 [47], miR-205 [48], miR-224-5P [49], miR-19b-3p, miR-130a-3p, miR-150-5p, miR-144-3p, miR-16-5p, miR-7a-5p, and miR-17-5p [50] can decrease the expression of ACSL4. It is conceivable but not yet demonstrated that these miRNAs can regulate ferroptosis by targeting ACSL4.…”

Ferroptosis in Cancer Treatment: Another Way to Rome

“…Acetaminophen enhances the sensitivity of erastin-induced ferroptosis by regulating the NRF2/HO-1 signaling pathway ( 48 ). Bromelain induces ROS-induced ferroptosis in Kras mutant colorectal cancer cells via the modulation of ACSL4 ( 49 ). Metadherin (MTDH) can inhibit the activities of GPX4 and SLC3A2 ( 50 ).…”

Targeting Long Chain Acyl-CoA Synthetases for Cancer Therapy

“…ACSs, depending upon the fatty chain length of their preferred substrate, are divided into five enzyme families: Short-chain (C2–C4), medium-chain (C4–C12), long-chain (C12–C22), bubblegum (C14–C24) and very long-chain acyl-CoA (C18–C26) [3]. The synthesis of fatty acyl-CoAs is required for different physiological processes, among which: Proliferation and migration [24,25,26], energy fueling [20,27,28], steroid synthesis, reduction of pro-apoptotic free fatty acids [29] and glucose tolerance [30].…”