Wogonin induces cellular senescence in breast cancer via suppressing TXNRD2 expression

Abstract

Cellular senescence contributes to tumor regression through both cell autonomous and non-autonomous mechanisms. Drugs inducing cancer cell senescence and modulating senescence-associated secretory phenotype (SASP) render advantage to the cancer treatment. Breast cancer remains the second most cause of female cancer mortality, among which triple-negative breast cancer (TNBC) has a more aggressive clinical course. Our study showed that in TNBC cell lines including MDA-MB-231 and 4T1 cells, moderate concentrations of wogonin (5, 7-dihydroxy-8-methoxy-2-phenyl-4h-1-benzopyran-4-one) (50-100 μM) not only induced permanent proliferation inhibition, but also increased P16 expression, β-galactosidase activity, senescence-associated heterochromatin foci and SASP, which are the typical characteristics of cellular senescence. Moreover, results showed that wogonin-induced senescence was partially attributed to the reactive oxygen species (ROS) accumulation upon wogonin treatment in MDA-MB-231 cells, since elimination of ROS by N-acetylcysteine (NAC) was able to repress wogonin-induced β-galactosidase activity. Mechanistically, wogonin reduced the expression of TXNRD2, an important antioxidant enzyme in controlling the levels of cellular ROS, by altering the histone acetylation at its regulatory region. In addition, senescent MDA-MB-231 cells induced by wogonin exhibited activated NF-κB and suppressed STAT3, which were recognized as regulators of SASP. SASP from these senescent cells suppressed tumor cell growth, promoted macrophage M1 polarization in vitro and increased immune cell infiltration in xenografted tumors in vivo. These results reveal another mechanism for the anti-breast cancer activity of wogonin by inducing cellular senescence, which suppresses tumor progression both autonomously and non-autonomously.

Nrf2 Signaling Pathway in Chemoprotection and Doxorubicin Resistance: Potential Application in Drug Discovery

“…Wogonin functions as an enhancer of ROS levels in inducing cell proliferation inhibition [193]. Wogonin can enhance efficacy of immune system in cancer eradication and promote macrophage M1 polarization [194]. In DOX-resistant breast cancer cells, wogonin suppresses defense system mediated via Nrf2 inhibition and decreasing expressions of HO-1 and NQO1 [195].…”

The role of functional polymorphisms in oxidative stress-related genes on early-stage breast cancer survival

“…In one study it was demonstrated that reduced expression of an antioxidant enzyme TXNRD2 may suppress BC progression. 13 However, in a hepatocellular carcinoma study, a lower level of TXNRD2 was associated with higher tumor stage. 24 In our study, we found that TXNRD2 rs1139793 common homozygote GG genotype, which is associated with low TXNRD2 protein level, 25 was a negative prognostic factor for DFS and MFS, while the rare A allele had a protective effect.…”

“…It has been found that reduced expression of an antioxidant enzyme TXNRD2 may suppress BC progression. 12,13 ROS superinduces expression of another oxidative stress-related activating transcription factor 3 (ATF3) gene. Under physiological conditions, ATF3 controls the expression of cell-cycle regulators and tumor suppressors, DNA repair, and apoptosis genes.…”

One-Two Punch Therapy for the Treatment of T-Cell Malignancies Involving p53-Dependent Cellular Senescence

“…Because of the central role of p53 in regulating cells' normal life activity, drug discovery concentrates on manipulating p53 and eradicating cancer cells. Wogonin is a well-known flavonoid and has a wide range of anticancer effects especially producing a better effect in hematologic malignancies [ 61 – 64 ]. However, although moderate and high concentrations of wogonin (over 40 μ M) had a better therapeutic effect, its insoluble characteristic and cytotoxicity in high doses were inescapable and limited its use in clinic.…”