Heme oxygenase‐1 inhibits rat and human breast cancer cell proliferation: mutual cross inhibition with indoleamine 2,3‐dioxygenase

Abstract

Heme oxygenase-1 (HO-1) is the rate limiting enzyme of heme catabolism whereas indoleamine 2,3 dioxygenase (IDO) catabolizes tryptophan through the kynurenine pathway. We analyzed the expression and biological effects of these enzymes in rat and human breast cancer cell lines. We show that rat (NMU and 13762) but not human cells (MCF-7 and T47D) express HO-1. When overexpressed, we found this enzyme to have anti-proliferative and proapoptotic effects by antioxidant mechanisms in these four cell lines. We show that IDO is expressed by rat and human breast cancer cells. IDO inhibition with 1-MT and siRNA leads to diminished proliferation in rat cells. In contrast, HO-1 negative human cell lines increase proliferation upon IDO inhibition. Since we also demonstrate that IDO inhibits the anti-proliferative HO-1, we propose that IDO has opposite effects on proliferation depending on the coexpression or not of HO-1. We also describe that HO-1 inhibits IDO at the post-translational level through heme starvation. In vivo, we show that rat normal breast expresses HO-1 and IDO. In contrast, N-nitrosomethylurea-induced breast adenocarcinomas only express IDO. In conclusion, we show that HO-1/IDO cross-regulation modulates apoptosis and proliferation in rat and human breast cancer cells.

Transcriptome Analysis of Piperlongumine-Treated Human Pancreatic Cancer Cells Reveals Involvement of Oxidative Stress and Endoplasmic Reticulum Stress Pathways

“…However, HMOX-1 can induce cancer cell apoptosis and inhibit tumor cell motility. 30,31 Recently, HMOX-1 expression was shown to be elevated by PL in breast cancer cells and a determining factor in the differential response of normal breast cells to PL. 32 Interestingly, PL silenced ATP-binding cassette subfamily B, member 10 (ABCB10) expression.…”

Indoleamine 2,3 dioxygenase–mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen‐induced arthritis

“…Because inhibition of NO production can ameliorate CIA depending on the time and route of delivery (36), it can be speculated that NO-IDO interactions limit the activation of IDO in the course of CIA. Similarly, HO-1-dependent generation of antioxidant compounds and consumption of the heme group can inhibit the activation of IDO, while inhibition of HO-1 has therapeutic effects in CIA (37,38).…”

Heme oxygenase-1 inhibits breast cancer invasion via suppressing the expression of matrix metalloproteinase-9

“…An increase in intracellular ROS level was detected in tumors, and stimulation of the proliferation and invasion of tumor cells with inducing MMP-9 activation by ROS has been identified (19,20). HO-1 induction has been reported to reduce intracellular ROS level (14,16,21). Our previous study indicated that HO-1 induction protected macrophages and glioma cells from hydrogen peroxide -induced apoptosis (14,21).…”

“…Induction of the HO-1 protein has been reported to protect against a variety of stress conditions such as hydrogen peroxide, cisplatin, UV irradiation, and inflammatory cytokine-mediated cell damage (12 -15). HO-1 has also been shown to inhibit the proliferation and induce apoptosis in several cancer cells such as breast carcinoma cells (16). Induction of HO-1 by the chemopreventive agent sulforaphane contributes to suppression of tumor cell growth by increasing the antioxidant response genes of hepatoma and breast cancer cells (17,18).…”