Abstract. Ursolic acid (UA), a natural pentacyclic triterpenoid compound, has been demonstrated to induce apoptosis in various tumors. The aim of the present study was to elucidate the molecular mechanisms of UA-induced apoptosis in HeLa cells. Here, we reported that UA induced apoptosis through the mitochondrial intrinsic pathway in HeLa cells, as shown by release of cytosol cytochrome c, activation of caspase-9 and -3, reduction of Bcl-2 and Bcl-xL, and increase of Bax and Bak. UA down-regulated the phosphorylation of ERK1/2 and p38, whereas phosphorylation of JNK was unchanged. The roles of ERK1/2 and p38 were further confirmed using the ERK1/2 inhibitor (U0126) and p38 inhibitor (SB203580). U0126 markedly increased UA-induced the Bax/Bcl-2 ratio, the increase of cytosol cytochrome c, and the levels of cleaved caspase-3, but SB203580 had little effects on the above characters, suggesting the ERK1/2 signaling pathway is required for apoptosis. Furthermore, UA up-regulated DUSP 1, 2, 4, 5, 6, 7, 9, and 10 mRNA expressions, which may be a clue for the role of dephosphorylation of ERK1/2 and p38. These data suggested that the apoptotic mechanism of UA treatment in HeLa cells was through the mitochondrial intrinsic pathway and closely associated with the suppression of the ERK1/2 signaling pathway.

Luteolin, an active component of traditional Chinese medicine, exhibits potential for anti-tumor proliferation; however, the molecular events occurring in such process and the signal transduction pathways involved are currently unknown. Our group previously reported that luteolin inhibited proliferation and induced apoptosis in the gastric cancer cell line BGC-823. The aim of the present study was to investigate the mechanism by which the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling pathways regulate the apoptosis in vitro of BGC-823 cells following treatment with luteolin. It was observed that luteolin induced apoptosis through the intrinsic pathway by increasing the levels of caspase-3, caspase-9 and cytochrome c, and the ratio of B-cell lymphoma (Bcl)-2 associated X protein (Bax) to Bcl-2. Luteolin suppressed the phosphorylation of extracellular signal-regulated kinase in the MAPK signaling pathway, as well as suppressing the phosphorylation of AKT, PI3K and mechanistic target of rapamycin in the PI3K signaling pathway. In addition, luteolin combined with LY294002 markedly increased the Bax/Bcl-2 ratio, while when combined with U0126, luteolin had less effects on the Bax/Bcl-2 ratio compared with luteolin treatment alone, suggesting that both the MAPK and PI3K signaling pathways are involved in the apoptosis induced by luteolin. Furthermore, luteolin attenuated the MAPK and PI3K signaling pathways by increasing the expression of specific dual-specificity phosphatases and decreasing the expression of chemokine (C-X-C motif) ligand 16 at the messenger RNA level, respectively. Taken together, the present results demonstrate that luteolin is a potential chemotherapeutic agent against gastric cancer by exerting a dual inhibition on the MAPK and PI3K signaling pathways.

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