Akt-Mediated Cisplatin Resistance in Ovarian Cancer: Modulation of p53 Action on Caspase-Dependent Mitochondrial Death Pathway

Yang, Xiaokui; Fraser, Michael; Moll, Ute M.; Basak, Ajoy; Tsang, Benjamin K.

doi:10.1158/0008-5472.can-05-0425

Cited by 236 publications

(224 citation statements)

References 42 publications

Supporting

Mentioning

208

Contrasting

Order By: Relevance

“…Immunoblotting analysis of cytoplasmic fraction revealed that expression of constitutively active Akt reduced HtrA2/Omi release from the mitochondria into the cytosol more than 1 fold (Fig. 6C), which is consistent with a recent report (40) showing inhibition of HtrA2/Omi release by expression of constitutively active Akt2 in A2780S cells. Taken collectively, we conclude that Akt abrogates HtrA2/Omi pro-apoptotic function through phosphorylation of serine 212 in cytoplasm and inhibition of its release from the mitochondria (Fig.…”

Section: Akt Abrogates Htra2/omi Pro-apoptotic Function Through Phospsupporting

confidence: 92%

Akt Attenuation of the Serine Protease Activity of HtrA2/Omi through Phosphorylation of Serine 212

Yang

Sun

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

The serine protease HtrA2/Omi is released from the mitochondria into the cytosol following apoptosis stimuli, leading to the programmed cell death in caspase-dependent and -independent manners. The function of HtrA2/Omi closely relates to its protease activity, which is required for cleavage of its substrate such as the members of the X-linked inhibitor of apoptotic protein family. However, the regulation of HtrA2/Omi by signaling molecule has not been documented. Here we report that serine/threonine kinases Akt1 and Akt2 phosphorylate mitochondria-released HtrA2/Omi on serine 212 in vivo and in vitro, which results in attenuation of its serine protease activity and pro-apoptotic function. Abolishing HtrA2/Omi phosphorylation by Akt through mutation of serine 212 to alanine (HtrA2/Omi-S212A) retains its serine protease activity and induces more apoptosis as compared with wild-type HtrA2/ Omi. Conversely, HtrA2/Omi-S212D, a mutant mimicking phosphorylation, lost the protease activity and failed to induce the programmed cell death. Furthermore, the phosphorylated HtrA2/Omi fails to cleave X-linked inhibitor of apoptotic protein without interfering with their complex formation. In addition, Akt inhibits the release of HtrA2/Omi from the mitochondria into the cytoplasm in response to cisplatin treatment. These data reveal for the first time that HtrA2/Omi is directly regulated by Akt and provide a mechanism by which Akt induces cell survival at post-mitochondrial level.

show abstract

Section: Akt Abrogates Htra2/omi Pro-apoptotic Function Through Phospsupporting

confidence: 92%

Akt Attenuation of the Serine Protease Activity of HtrA2/Omi through Phosphorylation of Serine 212

Yang

Sun

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Bax promotes apoptosis by enhancing the release of mitochondrial proteins including cytochrome c and Smac/DIABLO. Through transcription-independent pathways, p53 has a direct apoptogenic role where it translocates to mitochondria in response to cellular stress, resulting in apoptosis via interaction with antiapoptotic Bcl-2 and Bcl-X L proteins that alter the mitochondrial membrane potential and induce cytochrome c and Smac release into the cytosol with resultant caspase activation (72,75).…”

Section: Discussionmentioning

confidence: 99%

Involvement of Bcl-2 family members, phosphatidylinositol 3'-kinase/AKT and mitochondrial p53 in curcumin (diferulolylmethane)-induced apoptosis in prostate cancer

Shankar

Srivastava²

2007

Int J Oncol

132

141

View full text Add to dashboard Cite

Abstract. Curcumin (diferulolylmethane), an active ingredient derived from the rhizome of the plant Curcuma longa, has anticancer activity in vitro and in vivo. Although curcumin possesses chemopreventive properties against several types of cancer, the molecular mechanisms by which it inhibits cell growth and induces apoptosis are not clearly understood. Our data revealed that curcumin inhibited growth and induced apoptosis in androgen-dependent and -independent prostate cancer cells, but had no effect on normal human prostate epithelial cells. Curcumin downregulated the expression of Bcl-2, and Bcl-X L and upregulated the expression of p53, Bax, Bak, PUMA, Noxa, and Bim. Curcumin upregulated the expression of p53 as well as its phosphorylation at serine 15, and acetylation in a concentration-dependent manner. Acetylation of histone H3 and H4 was increased in cells treated with curcumin, suggesting histone modification may regulate gene expression. Treatment of LNCaP cells with curcumin resulted in translocation of Bax and p53 to mitochondria, production of reactive oxygen species, drop in mitochondrial membrane potential, release of mitochondrial proteins (cytochrome c, Smac/DIABLO and Omi/HtrA2), activation of caspase-3 and induction of apoptosis. Furthermore, curcumin inhibited expression of phosphatidylinositol-3 kinase (PI3K) p110 and p85 subunits, and phosphorylation of Ser 473 AKT/PKB. Downregulation of AKT by inhibitors of PI3K (Wortmannin and LY294002) and AKT, or by dominant negative AKT increased curcumininduced apoptosis, whereas transfection of constitutively active AKT attenuated this effect. Similarly, wild-type phosphatase and tensin homolog deleted from chromosome 10 (PTEN) enhanced curcumin-induced apoptosis and, in contrast, inactive PTEN (G129E and G129R) inhibited curcumin-induced apoptosis. Overexpression of constitutively active AKT inhibited curcumin-induced p53 translocation to mitochondria, and Smac release to cytoplasm, whereas inhibition of AKT by dominant negative AKT enhanced curcumin-induced p53 translocation to mitochondria and Smac release. Our study establishes a role for AKT in modulating the direct action of p53 on the caspasedependent mitochondrial death pathway and suggests that these important biological molecules interact at the level of the mitochondria to influence curcumin sensitivity. These properties of curcumin strongly suggest that it could be used as a cancer chemopreventive agent.

show abstract

“…[19][20][21][22][23] Upon release from mitochondria, AIF and EndoG translocate to the nucleus where they cause DNA fragmentation, 16,17 provoking apoptosis in a caspase-independent manner. 24,25 Cisplatin also has been shown to induce apoptosis through the mitochondrial release of proapoptotic molecules, including cytochrome c, [26][27][28] Omi/HtrA2, 29 Smac/Diablo, 30,31 and AIF. 19,30 However, the mechanisms by which cisplatin initiates apoptosis in cancer cells are not completely understood.…”

Section: Introductionmentioning

confidence: 99%

Reactive oxygen species‐dependent EndoG release mediates cisplatin‐induced caspase‐independent apoptosis in human head and neck squamous carcinoma cells

Kim

Lee

Jeong

et al. 2007

Intl Journal of Cancer

View full text Add to dashboard Cite

Cisplatin is a chemotherapeutic agent that is widely used to treat cancers such as head and neck squamous cell carcinoma (HNSCC). Previously, we have reported that cisplatin induced an early caspase-dependent apoptosis (8 hr) in a HNSCC cell, HN4. In this study, we examined a late caspase-independent apoptosis as well as an early caspase-dependent apoptosis in cisplatintreated HN4 cells. While z-VAD-fmk, a pan-caspase inhibitor, blocked the caspase activities and protected cells from the early apoptosis, it did not provide protection against delayed apoptosis occurring after extended exposure (16 hr) to cisplatin, suggesting that the delayed apoptotic response in the presence of z-VAD-fmk was caspase-independent. Cisplatin treatment induced reactive oxygen species (ROS) generation, loss of the mitochondrial membrane potential (MMP) and nuclear translocation of endonuclease G (EndoG). Small interfering RNA mediated-knockdown of EndoG significantly protected cells from the delayed apoptosis induced by cisplatin in the presence of z-VAD-fmk. Overexpression of Bcl-2 in HN4 cells prevented loss of MMP, nuclear translocation of EndoG and protected cells from the delayed apoptosis induced by cisplatin in the presence of z-VAD-fmk. Pretreatment with N-acetyl-L-cysteine (NAC), a ROS scavenger, prevented both ROS generation, loss of the MMP and nuclear translocation of EndoG. Together, our data indicate that cisplatin treatment induced ROS-mediated loss of the MMP, and, then, the nuclear translocation of EndoG, which played a crucial role in caspase-independent apoptosis of HN4 cells in the presence of z-VAD-fmk. This is the first report about the involvement of EndoG in cisplatin-induced caspase-independent apoptosis of cells. ' 2007 Wiley-Liss, Inc.

show abstract

Akt-Mediated Cisplatin Resistance in Ovarian Cancer: Modulation of p53 Action on Caspase-Dependent Mitochondrial Death Pathway

Cited by 236 publications

References 42 publications

Akt Attenuation of the Serine Protease Activity of HtrA2/Omi through Phosphorylation of Serine 212

Akt Attenuation of the Serine Protease Activity of HtrA2/Omi through Phosphorylation of Serine 212

Involvement of Bcl-2 family members, phosphatidylinositol 3'-kinase/AKT and mitochondrial p53 in curcumin (diferulolylmethane)-induced apoptosis in prostate cancer

Reactive oxygen species‐dependent EndoG release mediates cisplatin‐induced caspase‐independent apoptosis in human head and neck squamous carcinoma cells

Contact Info

Product

Resources

About