Anti-Melanophoren Stimulierendes Hormon polyclonal antibody

Death receptor Fas-mediated apoptosis not only eliminates nonspecific and autoreactive B cells but also plays a major role in antitumor immunity. However, the possible mechanisms underlying impairment of Fas-mediated induction of apoptosis during lymphomagenesis remain unknown. In this study, we employed our developed syngeneic lymphoma model to demonstrate that downregulation of Fas is required for both lymphoma development and lymphoma cell survival to evade immune cytotoxicity. CD40 signal activation significantly restored Fas expression and thereby induced apoptosis after Fas ligand treatment in both mouse and human lymphoma cells. Nevertheless, certain human lymphoma cell lines were found to be resistant to Fas-mediated apoptosis, with Livin (melanoma inhibitor of apoptosis protein; ML-IAP) identified as a driver of such resistance. High expression of Livin and low expression of Fas were associated with poor prognosis in patients with aggressive non-Hodgkin's lymphoma. Livin expression was tightly driven by bromodomain and extraterminal (BET) proteins BRD4 and BRD2, suggesting that Livin expression is epigenetically regulated in refractory lymphoma cells to protect them from Fas-mediated apoptosis. Accordingly, the combination of CD40-mediated Fas restoration with targeting of the BET proteins-Livin axis may serve as a promising immunotherapeutic strategy for refractory B-cell lymphoma. Significance: These findings yield insights into identifying risk factors in refractory lymphoma and provide a promising therapy for tumors resistant to Fas-mediated antitumor immunity.

Malignant melanoma is a kind of highly invasive and deadly diseases. The BRAF inhibitor (BRAFi) such as vemurafenib could achieve a high response rate in melanoma patients with BRAF(V600E)mutation. However, melanoma cells could easily develop resistance as well as addiction to BRAFi. Based on the drug addiction, intermittent treatment has been proposed to select against BRAFi-resistant melanoma cells. Because different dosages of BRAFi might be used in patients, it is necessary to know about the relationship between drug dosage and the degree of addiction. To address the problem, four drug-resistant melanoma cell sublines (A375/R0.5, A375/R2.0, M14/R0.5 and M14/R2.0) were established by continuously exposure of melanoma A375 or M14 cells to 0.5 or 2.0 mu M vemurafenib. Vemurafenib withdrawal resulted in much stronger suppression on clone formation in A375/R2.0 and M14/R2.0, compared with A375/R0.5 and M14/R0.5, respectively. Meanwhile, stronger upregulation of ERK1/2-FRA-1 pathway could be observed in A375/R2.0 and M14/R2.0. Further detection showed that some proinflammatory cytokines downstream of ERK1/2-FRA-1 pathway were upregulated after drug withdrawal, and the conditioned medium collected from the resistant A375 cells could inhibit clone formation. Furthermore, vemurafenib withdrawal resulted in suppressed cell proliferation rather than cell senescence, with stronger effect on A375/R2.0 compared with A375/R0.5. This study suggested that the depth of vemurafenib addiction in resistant melanoma cells is positively correlated to the drug dosage, which might be underpinned by the ERK1/2-FRA-1 pathway and the related cytokines.