Role of Activating Transcription Factor 3 on TAp73 Stability and Apoptosis in Paclitaxel-Treated Cervical Cancer Cells

Oh, Yeo Kyoung; Lee, Hyun Jung; Jeong, Mihee; Rhee, Marie; Mo, Jiwon; Song, E; Lim, Joong-Yeon; Choi, Kyunghee; Jo, Inho; Park, Sang Ick; Gao, Bin; Kwon, Yongil; Kim, Won‐Ho

doi:10.1158/1541-7786.mcr-07-0297

Cited by 30 publications

(23 citation statements)

References 44 publications

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“…Our study showed that the cell death inducing mechanism by hGal9 uses ATF3, a member of the ATF/CREB family of transcription factors that functions as a tumor suppressor (25)(26)(27)(28)(29), but not p53 or Bim, the major proapoptotic factors in cell death induced by conventional genotoxic agents or Bcr-Abl TKIs. This implies that hGal9 is effective against CML cells that have lost their addiction to Bcr-Abl TK activity or their functional p53.…”

Section: Discussionmentioning

confidence: 78%

Targeting Activating Transcription Factor 3 by Galectin-9 Induces Apoptosis and Overcomes Various Types of Treatment Resistance in Chronic Myelogenous Leukemia

Kuroda

Yamamoto

Nagoshi

et al. 2010

Molecular Cancer Research

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Tyrosine kinase inhibitors (TKI) against Bcr-Abl are the first-line therapeutics for chronic myelogenous leukemia (CML). However, the resistance to Bcr-Abl TKIs is induced in leukemic cells not only by loss of sensitivity to TKIs through Bcr-Abl-related molecular mechanisms but also by loss of addiction to Bcr-Abl TK activity by acquiring Bcr-Abl-unrelated additional oncogenic mutations. Therefore, the identification of an additional therapeutic target has been anticipated for achievement of a complete cure and to overcome resistance to treatment. We here showed that modified human Galectin-9 (hGal9), a lectin that show specific affinity for β-galactosides, inhibits the proliferation of five CML-derived cell lines by inducing apoptosis at their IC 50 s from 17.5 to 164.9 nmol/L. Our study revealed that activating transcription factor 3 (ATF3), a member of the ATF/ cAMP-responsive element binding protein family transcription factors, is the critical mediator for cell killing by hGal9, and that Noxa is one of the downstream effector molecules of ATF3. Bim, on the other hand, the BH3-only protein essential for apoptosis by Bcr-Abl TKIs, was not associated with hGal9-induced cell death. ATF3-mediated cell death by hGal9 was not hampered by the absence of p53, the presence of mutant Abl T315I , or by P-glycoprotein overexpression. In addition, hGal9 showed the additive growth-inhibitory effect with imatinib on CML cell lines.

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Section: Discussionmentioning

confidence: 78%

Targeting Activating Transcription Factor 3 by Galectin-9 Induces Apoptosis and Overcomes Various Types of Treatment Resistance in Chronic Myelogenous Leukemia

Kuroda

Yamamoto

Nagoshi

et al. 2010

Molecular Cancer Research

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“…The incomplete suppression of apoptosis by the p53 shRNA might be due to the residue p53, effects of ATF3 on p53-independent E6 functions (e.g. repression of pro-apoptotic Bak and Bax) (8,9), or ATF3-mediated activation of other p53 family members such as p73 (33). We therefore concluded that ATF3 can activate p53 and promote p53-mediated cell cycle arrest and apoptosis in HPV-positive cells.…”

Section: Atf3 Directlymentioning

confidence: 81%

Activating Transcription Factor 3 Activates p53 by Preventing E6-associated Protein from Binding to E6

Wang¹,

Mo²,

Ren

et al. 2010

Journal of Biological Chemistry

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Genomic integration of human papillomavirus (HPV) DNA accounts for more than 90% of cervical cancers. High-risk genital HPVs encode E6 proteins that can interact with a cellular ubiquitin ligase E6-associated protein (E6AP) and target the tumor suppressor p53 for ubiquitin-mediated proteolysis. Currently, how this critical event is regulated is largely unknown. Here we report that activating transcription factor 3 (ATF3), a broad DNA damage sensor whose expression is frequently downregulated in cervical cancer, interacted with E6 and prevented p53 from ubiquitination and degradation mediated by the viral protein. Consistent with its role as a potent E6 antagonist, ATF3 expressed enforcedly in HPV-positive SiHa cells activated p53, leading to expression of p53-target genes (e.g. p21 and PUMA), cell cycle arrest and apoptotic cell death. The leucine zipper domain of ATF3 appears indispensable for these effects as an ATF3 mutant lacking this domain failed to interact with E6 and activate p53 in the cervical cancer cells. The prevention of p53 degradation was unlikely caused by binding of ATF3 to the tumor suppressor, but rather was a consequence of disruption of the E6-E6AP interaction by ATF3. These results indicate that ATF3 plays a key role in a mechanism defending against HPV-induced carcinogenesis, and could serve as a novel therapeutic target for HPV-positive cancers. Human papillomavirus (HPV)3 infection is a major risk factor for cervical cancer (1, 2). Genomic integration of HPV DNA, occurring in more than 90% of cervical cancers, results in expression of a viral protein E6, which in turn inactivates the tumor suppressor p53 by driving its proteolysis (3). The E6 protein can bind to p53 at both the C terminus and the central DNA-binding region (4) and recruit a cellular protein E6AP to p53 (5, 6). E6AP belongs to the HECT family of E3 ubiquitin ligases and can catalyze the addition of ubiquitin moieties to p53, leading to its degradation by the 26 S proteasomes (6). Because the p53 gene is rarely mutated in cervical cancer, the E6-mediated degradation serves as the major mechanism inactivating p53 and promoting cervical carcinogenesis (7).In addition to p53 and E6AP, the E6 protein interacts with many other cellular proteins including Bak (8), Bax (9), CBP/ p300 (10), and BRCA1 (11), presumably through the four CXXC motifs sparsely distributed in the viral protein (12). These interactions account for the oncogenic activities of E6, which include not only promoting transformation but also enhancing cell proliferation and survival (13). Therefore, it is important to dissect the E6 interaction network for a better understanding of the molecular basis for cervical cancer and identification of therapeutic targets for the disease.ATF3 is a member of the ATF/CREB family of transcription factors and can be rapidly induced by DNA damage and other oncogenic stimuli (14,15). Whereas consequences of ATF3 induction are unclear, it is often assumed that ATF3 functions as a transcription factor to regulate gene expressio...

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“…Taxol shows great efficacy against malignant tumors especially in cervical, breast, and ovarian cancer [1,2]. Taxol acts by binding to tubulin and by promoting its assembly into microtubules.…”

Section: Introductionmentioning

confidence: 99%

Triterpenoid pristimerin synergizes with taxol to induce cervical cancer cell death through reactive oxygen species-mediated mitochondrial dysfunction

Eum¹,

Byun²,

Yoon³

et al. 2011

Anti-Cancer Drugs

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A combined treatment with conventional chemotherapies can enhance the effectiveness of chemotherapeutic agents against cancers. Here, we have shown that the naturally occurring triterpenoids synergistically enhance the response of cervical cancer cells to taxol. Of the triterpenoid compounds, pristimerin enhanced the anticancer effect of taxol with the highest efficiency by combination. Pristimerin synergizes with taxol to inhibit clonogenic survival and tumor growth in nude mice, and to enhance cell death in cervical cancer cells. A combined treatment with taxol and pristimerin induced cervical cancer cell death by increasing intracellular reactive oxygen species levels, upregulation of death receptor death receptor 5 (DR5), activation of Bax, and dissipation of mitochondrial membrane potential. Treatment with N-acetyl-L-cysteine, a thiol-containing antioxidant completely blocked combined treatment-induced Bax translocation as well as DR5 upregulation. Moreover, inhibition of Jun N-terminal kinase/c-Jun pathway attenuated cell death by blocking DR5 upregulation and Bax activation. These results indicate that the triterpenoid, pristimerin, synergistically enhances taxol response of cervical cancer cells through DR5 expression and Bax activation. Furthermore, the reactive oxygen species-dependent activation of the Jun N-terminal kinase/c-Jun pathway is required for the DR5 upregulation and Bax activation. The molecular mechanism revealed by this study may aid in the design of future combination cancer therapies against cells with intrinsically reduced sensitivity to taxol.

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Role of Activating Transcription Factor 3 on TAp73 Stability and Apoptosis in Paclitaxel-Treated Cervical Cancer Cells

Cited by 30 publications

References 44 publications

Targeting Activating Transcription Factor 3 by Galectin-9 Induces Apoptosis and Overcomes Various Types of Treatment Resistance in Chronic Myelogenous Leukemia

Targeting Activating Transcription Factor 3 by Galectin-9 Induces Apoptosis and Overcomes Various Types of Treatment Resistance in Chronic Myelogenous Leukemia

Activating Transcription Factor 3 Activates p53 by Preventing E6-associated Protein from Binding to E6

Triterpenoid pristimerin synergizes with taxol to induce cervical cancer cell death through reactive oxygen species-mediated mitochondrial dysfunction

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