Abstract
BackgroundApigenin is a flavonoid widely distributed in plant kingdom that exerts cytotoxic effects against a variety of solid and haematological cancers. In this study, we investigated the effect of apigenin against primary effusion lymphoma (PEL), a KSHV-associated B cell lymphoma characterized by a very aggressive behavior, displaying constitutive activation of STAT3 as well as of other oncogenic pathways and harboring wtp53.MethodsCell death was assessed by trypan blue exclusion assay, FACS analysis as well as by biochemical studies. The latter were also utilized to detect the occurrence of autophagy and the molecular mechanisms leading to the activation of both processes by apigenin. FACS analysis was used to measure the intracellular ROS utilizing DCFDA.ResultsWe show that apigenin induced PEL cell death and autophagy along with reduction of intracellular ROS. Mechanistically, apigenin activated p53 that induced catalase, a ROS scavenger enzyme, and inhibited STAT3, the most important pro-survival pathway in PEL, as assessed by p53 silencing. On the other hand, STAT3 inhibition by apigenin resulted in p53 activation, since STAT3 negatively influences p53 activity, highlighting a regulatory loop between these two pathways that modulates PEL cell death/survival.ConclusionThe findings of this study demonstrate that apigenin may modulate pro-apoptotic and pro-survival pathways representing a valid therapeutic strategy against PEL.
Highlights
Apigenin is a flavonoid widely distributed in plant kingdom that exerts cytotoxic effects against a variety of solid and haematological cancers
Based on this knowledge and on the reports showing that apigenin can target both STAT3 and p53 in cancer cells, in this study we investigated the effect of apigenin in primary effusion lymphoma (PEL) cells that display constitutive STAT3 activation and wtp53, and the underlying mechanisms [21]
We found that apigenin was able to reduce PEL cell survival in a dose dependent fashion while it slightly affected B cell survival, as indicated by the trypan-blue exclusion assay (Fig. 1a and d)
Summary
Apigenin is a flavonoid widely distributed in plant kingdom that exerts cytotoxic effects against a variety of solid and haematological cancers. Several studies have reported that apigenin can be used to prevent or successfully control tumor progression in vivo, in several animal models [2] These effects have been shown to occur either through the activation of the p53 oncosuppressor gene [2, 3] or the inhibition of oncogenic pathways, such as NFkB [4], HIF1alfa [5] and AKT [6]. It has been reported that the loss of p53 function activates JAK2STAT3 signaling to promote pancreatic tumor growth and gemcitabine resistance [22] All these studies suggest a reciprocal influence between p53 and STAT3 in cancer. We evaluated whether apigenin, previously reported to interfere with AKT activation, could affect autophagy in PEL cells
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