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.

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Pegylated interferon-alpha (PegIFNα) therapy has limited effectiveness in hepatitis B e-antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. However, the mechanism underlying this failure is poorly understood. We aimed to investigate the influence of bile acids (BAs), especially taurocholic acid (TCA), on the response to PegIFNα therapy in CHB patients. Here, we used mass spectrometry to determine serum BA profiles in 110 patients with chronic HBV infection and 20 healthy controls (HCs). We found that serum BAs, especially TCA, were significantly elevated in HBeAg-positive CHB patients compared with those in HCs and patients in other phases of chronic HBV infection. Moreover, serum BAs, particularly TCA, inhibited the response to PegIFNα therapy in HBeAg-positive CHB patients. Mechanistically, the expression levels of IFN-γ, TNF-α, granzyme B, and perforin were measured using flow cytometry to assess the effector functions of immune cells in patients with low or high BA levels. We found that BAs reduced the number and proportion and impaired the effector functions of CD3+CD8+ T cells and natural killer (NK) cells in HBeAg-positive CHB patients. TCA in particular reduced the frequency and impaired the effector functions of CD3+CD8+ T and NK cells in vitro and in vivo and inhibited the immunoregulatory activity of IFN-α in vitro. Thus, our results show that BAs, especially TCA, inhibit the response to PegIFNα therapy by impairing the effector functions of CD3+CD8+ T and NK cells in HBeAg-positive CHB patients. Our findings suggest that targeting TCA could be a promising approach for restoring IFN-α responsiveness during CHB treatment.

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Glioblastoma (GBM) is the most common type of primary adult brain tumor. Glioma stem cell (GSC) residence and Temozolomide (TMZ) resistance in GBM both contribute to poor patient outcome. TRAF4 is a scaffold protein with E3 ubiquitin ligase activity that has recently been discovered to promote invasion and metastasis in several malignancies, but the effects and functions of TRAF4 in GBM remain to be determined. Here, we report that TRAF4 is preferentially overexpressed in GSCs and is required for stem-like properties as well as TMZ sensitivity in GBM cells. TRAF4 specifically interacted with the N-terminal tail of Caveolin-1 (CAV1), an important contributor to the tumorigenicity of GBM cells. TRAF4 regulated CAV1 stability by preventing ZNRF1-mediated ubiquitination and facilitating USP7-mediated deubiquitination independently of its E3 ubiquitin ligase catalytic activity. TRAF4-mediated stabilization of CAV1 activated protumorigenic AKT/ERK1/2 signaling, and disruption of this axis resulted in defects in stemness maintenance. In addition, expression of TRAF4 and CAV1 was positively correlated and predicted poor prognosis in human GBM samples. Screening of common nervous system drugs identified Risperidone interaction with TRAF4, and Risperidone treatment resulted in the dissociation of TRAF4 and CAV1. Importantly, pharmacological inhibition of TRAF4 with Risperidone potently inhibited self-renewal, abrogated tumorigenicity, and reversed TMZ resistance in GBM. Overall, TRAF4-mediated stabilization of CAV1 promotes stemness and TMZ resistance in GBM, providing a therapeutic strategy that could improve patient outcomes.