The P2Y2/Src/p38/COX-2 pathway is involved in the resistance to ursolic acid-induced apoptosis in colorectal and prostate cancer cells

Limami, Youness; Pinon, Aline; Léger, David Y.; Pinault, Émilie; Delage, Christiane; Beneytout, Jean-Louis; Simon, Alain; Liagre, Bertrand

doi:10.1016/j.biochi.2012.04.006

Cited by 65 publications

(42 citation statements)

References 54 publications

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“…Furthermore, we showed recently that COX-2 positively regulated Akt signalling and enhanced survival of cancer cells exposed to anticancer agents (35). Numerous studies have shown that COX-2 expression prevents apoptosis in cancer cells, especially in colon (49,50) and prostate cancer (51)(52)(53). Here, we showed that Bl extract reduced significantly expression of COX-2 by a dose-dependent manner at 48-h treatment in HEL and K562 (COX-2 + ) cells (Fig.…”

Section: Resultssupporting

confidence: 57%

Berberis libanotica extract targets NF-κB/COX-2, PI3K/Akt and mitochondrial/caspase signalling to induce human erythroleukemia cell apoptosis

Diab

Fidanzi

Léger

et al. 2015

International Journal of Oncology

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Abstract. The aim of this study was to describe and understand the relationship between cyclooxygenase-2 (COX-2) expression and apoptosis rate in erythroleukemia cells after apoptosis induction by Berberis libanotica (Bl) extract. To achieve this goal we used erythroleukemia cell lines expressing COX-2 (HEL cell line) or not (K562 cell line). Moreover, we made use of COX-2 cDNA to overexpress COX-2 in K562 cells. In light of the reported chemopreventive and chemosensitive effects of natural products on various tumor cells and animal models, we postulated that our Bl extract may mediate their effects through apoptosis induction with suppression of cell survival pathways. Our study is the first report on the specific examination of intrinsic apoptosis and Akt/NF-κB/COX-2 pathways in human erythroleukemia cells upon Bl extract exposure. Even if Bl extract induced apoptosis of three human erythroleukemia cell lines, a dominant effect of Bl extract treatment on K562 cells was observed resulting in activation of the late markers of apoptosis with caspase-3 activation, PARP cleavage and DNA fragmentation. Whereas, we showed that Bl extract reduced significantly expression of COX-2 by a dose-dependent manner in HEL and K562 (COX-2 + ) cells. Furthermore, in regard to our results, it is clear that the simultaneous inhibition of Akt and NF-κB signalling can significantly contribute to the anticancer effects of Bl extract in human erythroleukemia cells. We observed that the Bl extract is clearly more active than the berberine alone on the induction of DNA fragmentation in human erythroleukemia cells.

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Section: Resultssupporting

confidence: 57%

Berberis libanotica extract targets NF-κB/COX-2, PI3K/Akt and mitochondrial/caspase signalling to induce human erythroleukemia cell apoptosis

Diab

Fidanzi

Léger

et al. 2015

International Journal of Oncology

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“…It has been reported that p38 MAPK and ERK1/2 pathways are important for glioma development (10)(11)(12). Previous studies have demonstrated that MAPKs (p38 MAPK and ERK1/2) also activate other signaling cascades, such as cyclooxygenase-2 (COX-2) (13,14), in a variety of cancer cell types. COX-2 expression is closely associated with tumor cell growth and is a crucial molecule in the development of malignant tumors, and angiogenesis (15,16), anti-apoptosis (17), invasiveness (18) and proliferation (19).…”

Section: Introductionmentioning

confidence: 99%

Exogenous hydrogen sulfide promotes C6 glioma cell growth through activation of the p38 MAPK/ERK1/2-COX-2 pathways

et al. 2015

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Abstract. Hydrogen sulfide (H 2 S) participates in multifarious physiological and pathophysiologic progresses of cancer both in vitro and in vivo.We have previously demonstrated that exogenous H 2 S promoted liver cancer cells proliferation/anti-apoptosis/angiogenesis/migration effects via amplifying the activation of NF-κB pathway. However, the effects of H 2 S on cancer cell proliferation and apoptosis are controversial and remain unclear in C6 glioma cells. The present study investigated the effects of exogenous H 2 S on cancer cells growth via activating p38 MAPK/ERK1/2-COX-2 pathways in C6 glioma cells. C6 glioma cells were treated with 400 µmol/l NaHS (a donor of H 2 S) for 24 h. The expression levels of phosphorylated (p)-p38 MAPK, total (t)-p38 MAPK, p-ERK1/2, t-ERK1/2, cyclooxygenase-2 (COX-2) and caspase-3 were measured by western blotting assay. Cell viability was detected by Cell Counting . Apoptotic cells were observed by Hoechst 33258 staining assay. Cell proliferation was directly detected under fully automatic inverted microscope. Exposure of C6 glioma cells to NaHS resulted in cell proliferation, as evidenced by an increase in cell viability. In addition, NaHS treatment reduced apoptosis, as indicated by the decreased apoptotic percentage and the cleaved caspase-3 expression. Importantly, exposure of the cells to NaHS increased the expression levels of p-p38 MAPK, p-ERK1/2 and COX-2. Notably, co-treatment of C6 glioma cells with 400 µmol/l NaHS and AOAA (an inhibitor of CBS) largely suppressed the above NaHS-induced effects. Combined treatment with NaHS and SB203580 (an inhibitor of p38 MAPK) or PD-98059 (an inhibitor of ERK1/2) resulted in the synergistic reduction of COX-2 expression and increase of caspase-3 expression, a decreased number of apoptotic cells, along with decreased cell viability. Combined treatment with NS-398 (an inhibitor of COX-2) and NaHS also resulted in the synergistic increase of caspase-3, a decreased in the number of apoptotic cells and the decrease in cell viability. The findings of the present study provide novel evidence that p38 MAPK/ERK1/2-COX-2 pathways are involved in NaHS-induced cancer cell proliferation and anti-apoptosis in C6 glioma cells.

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“…COX-2 has been shown to play an important role in apoptosis resistance and carcinogenesis, particularly in colon carcinogenesis [64,65]. Previous studies in our laboratory reported a role for COX-2 in resistance to apoptosis in colorectal and prostate cancer cells [66,67]. Here, we showed that RG003 reduced COX-2 expression in PC-3 cells; this inhibition can make cells more sensitive to TRAIL treatment.…”

Section: Discussionmentioning

confidence: 55%

2′-Hydroxy-4-methylsulfonylchalcone enhances TRAIL-induced apoptosis in prostate cancer cells

Ismail¹,

Fagnere²,

Limami³

et al. 2015

Anti-Cancer Drugs

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Prostate cancer is the most common malignant cancer in men and the second leading cause of cancer deaths. Previously, we have shown that 2'-hydroxy-4-methylsulfonylchalcone (RG003) induced apoptosis in prostate cancer cell lines PC-3 and DU145. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, some cancer cells are resistant to TRAIL treatment. PC-3 and LNCaP prostatic cancer cell lines have been reported to be resistant to TRAIL-induced apoptosis. Here, we show for the first time that RG003 overcomes TRAIL resistance in prostate cancer cells. RG003 can enhance TRAIL-induced apoptosis through DR5 upregulation and downregulation of Bcl-2, PI3K/Akt, NF-κB, and cyclooxygenase-2 (COX-2) survival pathways. When used in combined treatment, RG003 and TRAIL amplified TRAIL-induced activation of apoptosis effectors and particularly activation of caspase-8 and the executioner caspase-3, leading to increased poly-ADP-ribose polymerase cleavage and DNA fragmentation in prostate cancer cells. Furthermore, we showed that RG003 reduced COX-2 expression in cells. Previously, we showed that COX-2 was involved in resistance to an apoptosis mechanism; then, its inhibition by RG003 could render cells more sensitive to TRAIL treatment. We showed that nuclear factor-κB activation was inhibited after RG003 treatment. This inhibition was correlated with reduction in COX-2 expression and induction of apoptosis. Overall, we conclude, for the first time, that RG003 can enhance TRAIL-induced apoptosis in human prostate cancer cells. The significance of our in-vitro study with RG003 and TRAIL combined is very encouraging, suggesting the relevance of testing this combined treatment in xenograft animal models.

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The P2Y2/Src/p38/COX-2 pathway is involved in the resistance to ursolic acid-induced apoptosis in colorectal and prostate cancer cells

Cited by 65 publications

References 54 publications

Berberis libanotica extract targets NF-κB/COX-2, PI3K/Akt and mitochondrial/caspase signalling to induce human erythroleukemia cell apoptosis

Berberis libanotica extract targets NF-κB/COX-2, PI3K/Akt and mitochondrial/caspase signalling to induce human erythroleukemia cell apoptosis

Exogenous hydrogen sulfide promotes C6 glioma cell growth through activation of the p38 MAPK/ERK1/2-COX-2 pathways

2′-Hydroxy-4-methylsulfonylchalcone enhances TRAIL-induced apoptosis in prostate cancer cells

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