Autophagy is a tightly-regulated catabolic pathway involving degradation of cellular
proteins, cytoplasm and organelles. Recent evidence suggests that autophagy plays a potential role in cell death as a
tumor suppressor and that its induction especially in combination with apoptosis could be beneficial. It remains unclear if all
cancer cells behave the same mechanism when autophagy is induced. Although
mammalian target of rapamycin (mTOR) is well known as a negative regulator of autophagy, the relationship between
signal transducer and activator of transcription 3 (STAT3) and autophagy has not yet been investigated.
Oroxylin A, a natural mono-
flavonoid extracted from Scutellariae radix, is a promising therapeutic agent for treating multiple
cancers. Here we investigated the mechanism underlying the effect of
oroxylin A on
malignant glioma cells. We showed that
oroxylin A inhibited the proliferation of
malignant glioma cells by inducing autophagy in a dose- and time-dependent manner.
Oroxylin A treatment inhibits the AKT and ERK activation and the downstream phosphorylation level of mTOR and STAT3. In addition,
oroxylin A treatment decreases the expression of Notch-1 and myeloid cell leukemia-1 (Mcl-1) but upregulates
Beclin 1, the key
autophagy-related protein. 3-MA (autophagy inhibitor) or knockdown of
Beclin 1 partially can rescue cells from
oroxylin A-induced autophagic cell death. In contrast, knockdown of STAT3 aggravates
oroxylin A-induced autophagic cell death. Our data reveal an important role of autophagy in enhancing cell death induced by
oroxylin A and conclude that
oroxylin A exerts anti-
malignant glioma proficiency by inducing autophagy via the ERK/AKT-mTOR-STAT3-Notch signaling cascade.