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SA-β-Galactosidase-Based Screening Assay for the Identification of Senotherapeutic Drugs
Published on: June 28, 2019
Wogonin induces cellular senescence in breast cancer via suppressing TXNRD2 expression
Dawei Yang1, Qinglong Guo1, Yin Liang1
1State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, People's Republic of China.
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.
Insights
Wogonin induces cancer cell senescence in triple-negative breast cancer (TNBC) by affecting reactive oxygen species (ROS) and altering gene expression. This senescence suppresses tumor growth and enhances anti-tumor immunity.
Area of Science:
- Oncology
- Cell Biology
- Immunology
Background:
- Cellular senescence plays a role in tumor regression via autonomous and non-autonomous mechanisms.
- Targeting cancer cell senescence and its associated secretory phenotype (SASP) offers therapeutic advantages.
- Triple-negative breast cancer (TNBC) is aggressive and requires novel treatment strategies.
Purpose of the Study:
- To investigate the effect of wogonin on inducing cellular senescence in TNBC cells.
- To elucidate the molecular mechanisms underlying wogonin-induced senescence.
- To evaluate the impact of wogonin-induced senescence on tumor progression and the tumor microenvironment.
Main Methods:
- TNBC cell lines (MDA-MB-231, 4T1) were treated with varying concentrations of wogonin.
- Cellular senescence was assessed by measuring proliferation, P16 expression, β-galactosidase activity, and senescence-associated heterochromatin foci.
- Reactive oxygen species (ROS) levels were analyzed, and the role of N-acetylcysteine (NAC) was investigated.
- Gene expression, histone acetylation, NF-κB, and STAT3 signaling were examined.
- In vitro and in vivo models were used to assess the effects of senescent cells on tumor growth, macrophage polarization, and immune cell infiltration.
Main Results:
- Wogonin (50-100 μM) induced permanent proliferation inhibition and typical senescence markers in TNBC cells.
- Wogonin-induced senescence was partly mediated by ROS accumulation, involving the downregulation of the antioxidant enzyme TXNRD2 via altered histone acetylation.
- Senescent cells exhibited activated NF-κB and suppressed STAT3, leading to suppressed tumor growth, enhanced M1 macrophage polarization, and increased immune cell infiltration.
Conclusions:
- Wogonin effectively induces cellular senescence in TNBC cells, characterized by ROS accumulation and altered gene expression.
- Wogonin-mediated senescence suppresses tumor progression through both direct anti-proliferative effects and indirect modulation of the immune microenvironment.
- These findings highlight wogonin's potential as an anti-cancer agent for TNBC by leveraging senescence pathways.
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