Sensitization of melanoma cells for TRAIL-induced apoptosis by activation of mitochondrial pathways via Bax

Quast, Sandra-Annika; Berger, Anja; Plötz, Michael; Eberle, Jürgen

doi:10.1016/j.ejcb.2013.11.003

Cited by 28 publications

(32 citation statements)

References 83 publications

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“…Although the Bcl-xL and Bcl-2 proteins were highly expressed in control cells, hypoxia maintained the level of both proteins, whereas melatonin down-regulated their expression levels dose-dependently. Many studies have revealed that high levels of Bcl-xL and Bcl-2 may or may not inhibit TRAIL-induced apoptosis under hypoxia and propose that a decrease in anti-apoptotic proteins could be a possible mechanism for our present results [37,38,39,40]. Finally, we suggest that the matrix metalloproteinase (MMP) and bax translocation are a recovery mechanism for melatonin against hypoxic inhibition.…”

Section: Resultssupporting

confidence: 52%

Overcoming Hypoxic-Resistance of Tumor Cells to TRAIL-Induced Apoptosis through Melatonin

Lee

Moon

Park

2014

IJMS

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A solid tumor is often exposed to hypoxic or anoxic conditions; thus, tumor cell responses to hypoxia are important for tumor progression as well as tumor therapy. Our previous studies indicated that tumor cells are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell apoptosis under hypoxic conditions. Melatonin inhibits cell proliferation in many cancer types and induces apoptosis in some particular cancer types. Here, we examined the effects of melatonin on hypoxic resistant cells against TRAIL-induced apoptosis and the possible mechanisms of melatonin in the hypoxic response. Melatonin treatment increased TRAIL-induced A549 cell death under hypoxic conditions, although hypoxia inhibited TRAIL-mediated cell apoptosis. In a mechanistic study, hypoxia inducible factor-1α and prolyl-hydroxylase 2 proteins, which increase following exposure to hypoxia, were dose-dependently down-regulated by melatonin treatment. Melatonin also blocked the hypoxic responses that reduced pro-apoptotic proteins and increased anti-apoptotic proteins including Bcl-2 and Bcl-xL. Furthermore, melatonin treatment reduced TRAIL resistance by regulating the mitochondrial transmembrane potential and Bax translocation. Our results first demonstrated that melatonin treatment induces apoptosis in TRAIL-resistant hypoxic tumor cells by diminishing the anti-apoptotic signals mediated by hypoxia and also suggest that melatonin could be a tumor therapeutic tool by combining with other apoptotic ligands including TRAIL, particularly in solid tumor cells exposed to hypoxia.

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Section: Resultssupporting

confidence: 52%

Overcoming Hypoxic-Resistance of Tumor Cells to TRAIL-Induced Apoptosis through Melatonin

Lee

Moon

Park

2014

IJMS

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“…5 , butein, in combination with cisplatin, significantly enhanced the expression of p27 and decreased that of cyclin D1 compared to treatment with cisplatin alone, but had no effect on the expression of p21 (data not shown). Bax and Bcl-2 are important members of Bcl-2 family proteins and regulate mitochondrial involvement in apoptosis ( 19 , 20 ). Co-treatment with butein and cisplatin for 48 h resulted in increased expression levels of Bax, but reduced protein levels of Bcl-2 compared to treatment with cisplatin alone ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Butein sensitizes HeLa cells to cisplatin through the AKT and ERK/p38 MAPK pathways by targeting FoxO3a

Zhang

Yang

et al. 2015

International Journal of Molecular Medicine

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Drug resistance remains a major challenge in cancer therapy. Butein, a polyphenolic compound, has been shown to exhibit anticancer activity through the inhibition of the activation of the protein kinase B (PKB/AKT) and mitogen-activated protein kinase (MAPK) pathways, which are two pathways known to be involved in resistance to cisplatin. Hence, we hypotheiszed that butein may be a chemosensitizer to cisplatin. In the present study, we demonstrated that butein synergistically enhanced the growth inhibitory and apoptosis-inducing effects of cisplatin on HeLa cells. Moreover, the combination of butein and cisplatin led to G1 phase arrest. We then aimed to explore the underlying mechanisms. We found that butein inhibited the activation of AKT, extracellular signal-regulated kinase (ERKs) and p38 kinases in the presence of cisplatin. The use of the AKT inhibitor, LY294002, in combination with cisplatin, induced an increase in apoptosis compared to treatment with cisplatin alone, although this effect was not as prominent as that exerted by butein in combination with cisplatin. Of note, the inhibition of ERK or p38 MAPK by U0126 or SB203580, respectively, decreased the apoptosis induced by cisplatin; however, enhanced apoptotic effects were observed with the use of ERK/p38 MAPK inhibitor in combination with butein. These data suggest that the AKT and ERK/p38 MAPK pathways are involved in the synergistic effects of butein and cisplatin. Furthermore, co-treatment with butein and cisplatin promoted the nuclear translocation and expression of forkhead box O3a (FoxO3 or FoxO3a). FoxO3a may be the key molecule on which these pathways converge and is thus implicated in the synergistic effects of butein and cisplatin. This was further confirmed by the RNAi-mediated suppression of FoxO3a. FoxO3a target genes involved in cell cycle progression and apoptosis were also investigated, and combined treatment with butein and cisplatin resulted in the downregulation of cyclin D1 and Bcl-2 and the upregulation of p27 and Bax. In addition, the combination of both agents markedly inhibited tumor growth and increased the expression of FoxO3a in mouse tumor xenograft models of cervical cancer. Taken together, to the best of our knowledge, our results reveal for the first time that butein sensitizes cervical cancer cells to cisplatin in vitro and in vivo, and these effects of butien may be related to the inhibition of the activation of the AKT and ERK/p38 MAPK pathways by targeting FoxO3a.

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“…It is also revealed that Bax‐deficient human colon carcinoma cells are resistant to death‐receptor ligands, while Bax‐expressing sister clones are sensitive, indicating that Bax is essential for death receptor‐mediated apoptosis. Moreover, it has been reported that sensitization of melanoma for TNF‐related apoptosis‐inducing ligand (TRAIL) induced apoptosis appears to be particularly dependent on Bax . Knockdown of Bax prevents release of Smac from the mitochondria and thereby blocking TRAIL‐induced apoptosis .…”

Section: Function Of Bax and Its Associated Signalingmentioning

confidence: 99%

“…Moreover, it has been reported that sensitization of melanoma for TNF‐related apoptosis‐inducing ligand (TRAIL) induced apoptosis appears to be particularly dependent on Bax . Knockdown of Bax prevents release of Smac from the mitochondria and thereby blocking TRAIL‐induced apoptosis . Suppressed Bax activity is one of the major reasons of TRAIL resistance in melanoma …”

Section: Function Of Bax and Its Associated Signalingmentioning

confidence: 99%

Direct Activation of Bax Protein for Cancer Therapy

Liu

Ding

et al. 2015

Medicinal Research Reviews

208

141

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Bax, a central cell death regulator, is an indispensable gateway to mitochondrial dysfunction and a major pro-apoptotic member of the Bcl-2 family proteins that control apoptosis in normal and cancer cells. Dysfunction of apoptosis renders the cancer cell resistant to treatment as well as promotes tumorigenesis. Bax activation induces mitochondrial membrane permeabilization, thereby leading to the release of apoptotic factor cytochrome c and consequently cancer cell death. A number of drugs in clinical use are known to indirectly activate Bax. Intriguingly, recent efforts demonstrate that Bax can serve as a promising direct target for small-molecule drug discovery. Several direct Bax activators have been identified to hold promise for cancer therapy with the advantages of specificity and the potential of overcoming chemo- and radioresistance. Further investigation of this new class of drug candidates will be needed to advance them into the clinic as a novel means to treat cancer.

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Sensitization of melanoma cells for TRAIL-induced apoptosis by activation of mitochondrial pathways via Bax

Cited by 28 publications

References 83 publications

Overcoming Hypoxic-Resistance of Tumor Cells to TRAIL-Induced Apoptosis through Melatonin

Overcoming Hypoxic-Resistance of Tumor Cells to TRAIL-Induced Apoptosis through Melatonin

Butein sensitizes HeLa cells to cisplatin through the AKT and ERK/p38 MAPK pathways by targeting FoxO3a

Direct Activation of Bax Protein for Cancer Therapy

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