Tetrahydrocurcumin regulates the tumor immune microenvironment to inhibit breast cancer proliferation and metastasis via the CYP1A1/NF-κB signaling pathway

Abstract

The NF-κB signaling pathway is overactivated in tumor cells, and the activation of the NF-κB signaling pathway releases a large number of inflammatory factors, which enhance tumor immunosuppression and promote tumor metastasis. The cytochrome P450 (CYP450) system consists of important metabolic enzymes present in different tissues and progressive tumors, which may lead to changes in the pharmacological action of drugs in inflammatory diseases such as tumors. In this study, the anticancer effect of tetrahydrocurcumin (THC), an active metabolite of curcumin, on breast cancer cells and the underlying mechanism were investigated. Result showed that THC selectively inhibited proliferation and triggered apoptosis in breast cancer cells in a concentration- and time-dependent manner. Moreover, THC-induced cell apoptosis via a mitochondria-mediated pathway, as indicated by the upregulated ratio of Bax/Bcl-2 and reactive oxygen species (ROS) induction. In addition, THC could affect the CYP450 enzyme metabolic pathway and inhibit the expression of CYP1A1 and activation of the NF-κB pathway, thereby inhibiting the migration and invasion of breast cancer cells. Furthermore, after overexpression of CYP1A1, the inhibitory effects of THC on the proliferation, metastasis, and induction of apoptosis in breast cancer cells were weakened. The knockdown of CYP1A1 significantly enhanced the inhibitory effect of THC on the proliferation, metastasis, and apoptosis induction of breast cancer cells. Notably, THC exhibited a significant tumor growth inhibition and anti-pulmonary metastasis effect in a tumor mouse model of MCF-7 and 4T1 cells by regulating the tumor immunosuppressive microenvironment. Collectively, these results showed that TH could effectively trigger apoptosis and inhibit the migration of breast cancer cells via the CYP1A1/NF-κB signaling pathway, indicating that THC serves as a potential candidate drug for the treatment of breast cancer.

Fatty acids in cancer: Metabolic functions and potential treatment

“…In the CYP450 synthetic pathway, a variety of PUFAs serves as substrates to generate epoxides such as epoxyeicosatrienoic acids (EETs) and HETEs 140 . Among epoxides, EETs have been demonstrated to be associated with several cancers 39,127–129,136–138,153–178 . It has been reported that 14,15‐EET levels are significantly higher in breast cancer than in noncancerous tissue 127 .…”

“…For example, high levels of CYP1A1 can be detected in patients with smoking‐induced lung cancer 155 . Furthermore, overexpression of CYP1A1 in breast cancer can eliminate the drug effect of tetrahydrocurcumin 136 . In the meantime, the expression of CYP2J2 is also found to be upregulated in various forms of cancer cell lines, including lung cancer, prostate cancer, and kidney cancer 137 .…”

“…140 Among epoxides, EETs have been demonstrated to be associated with several cancers. 39,[127][128][129][136][137][138] It has been reported that 14,15-EET levels are significantly higher in breast cancer than in noncancerous tissue. 127 Moreover, EETs promote cancer cell proliferation and tumor angiogenesis, possibly by activating phosphorylation of EGFR and STAT3.…”

“…155 Furthermore, overexpression of CYP1A1 in breast cancer can eliminate the drug effect of tetrahydrocurcumin. 136 In the meantime, the expression of CYP2J2 is also found to be upregulated in various forms of cancer cell lines, including lung cancer, prostate cancer, and kidney cancer. 137 CYP3A4 shows a significant correlation with the survival of breast cancer patients.…”

The role of tetrahydrocurcumin in disease prevention and treatment

“…Numerous studies have shown that THC has great potential in a variety of diseases, including neurological diseases, cardiovascular system diseases, kidney diseases and cancer. Our research group also conducted a multidimensional evaluation of THC through animal studies and found that THC had potential therapeutic effects in cognitive impairment, 20,21 breast cancer, 22 skin photoaging, 23,24 melanin production, 25 type 2 diabetes, 26,27 colon cancer, 28 high-altitude cerebral oedema. 29 In addition, solid dispersion of THC was prepared, which effectively improved its bioavailability 30 and we further valuated its effect on metabolic syndrome, 31,32 Alzheimer's disease (AD) through animal experiments.…”