Apoptosis induced by proteasome inhibition in cancer cells: predominant role of the p53/PUMA pathway

Concannon, Caoimhín G.; Koehler, B; Reimertz, Christoph; Murphy, Brona M.; Bonner, Caroline; Thurow, N.; Ward, Manus W.; Villunger, Andreas; Strasser, Andreas; Kögel, Donat; Prehn, Jochen H.M.

doi:10.1038/sj.onc.1209974

Cited by 98 publications

(91 citation statements)

References 55 publications

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“…In certain cancer cells, the Food and Drug Administration (FDA)-approved proteasome inhibitor bortezomib can work through Bim and/or Bik, and collaborate with TRAIL (Nikrad et al, 2005;Tan et al, 2005), but in melanomas and myelomas and squamous cell carcinoma, it works instead through Noxa in a p53-independent manner (Fernandez et al, 2005;Qin et al, 2005;Fribley et al, 2006). In tumor cells with wild-type p53, however, proteasome inhibitors can instead act by driving p53-dependent expression of Puma (Concannon et al, 2006).…”

Section: Towards a More Rational Cancer Therapymentioning

confidence: 99%

The Bcl-2 apoptotic switch in cancer development and therapy

2007

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Section: Towards a More Rational Cancer Therapymentioning

confidence: 99%

The Bcl-2 apoptotic switch in cancer development and therapy

2007

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“…Although bortezomib has been shown to induce BAX (and BAK) conformation change (PerezGalan et al, 2006), studies examining the effect of bortezomib on BAX and BAK expression have not identified an increase in level of these proteins that might contribute to its proapoptotic efficacy (Table 1); furthermore, neither of the activator BH3-only proteins BID nor PUMA have been shown to be upregulated by bortezomib (Zhu et al, 2005b;Qin et al, 2006). PUMA has been shown recently, however, to be upregulated in a p53-dependent manner in response to the proteasome inhibitor epoxomicin (epoxo) (Concannon et al, 2007).…”

Section: Bax and Bak Are Activated By Bortezomibmentioning

confidence: 99%

BCL-2 family regulation by the 20S proteasome inhibitor bortezomib

Fennell

Chacko

Mutti³

2007

Oncogene

137

105

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Bortezomib (Velcade, PS341) was licensed in 2003 as a first-in-class 20S proteasome inhibitor indicated for treatment of multiple myeloma, and is currently being evaluated clinically in a range of solid tumours. The mechanisms underlying its cancer cell toxicity are complex. A growing body of evidence suggests proteasome inhibition-dependent regulation of the BCL-2 family is a critical requirement. In particular, the stabilization of BH3-only proteins BIK, NOXA and BIM, appear to be essential for effecting BAX-and BAK-dependent cell death. These mechanisms are reviewed and the implications for favourable novel drug interactions are highlighted.

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“…PUMA plays an essential role in cell apoptosis induced by a variety of stimuli . Previous studies have shown that PUMA was necessary and sufficient for endoplasmic reticulum stress-induced apoptosis and that it also was activated in cells subjected to proteasome inhibition (Reimertz et al, 2003;Concannon et al, 2007). Cells lacking PUMA are resistant to several death stimuli (Clarke et al, 1993;Strasser et al, 1994;Jeffers et al, 2003;Villunger et al, 2003;.…”

Section: Introductionmentioning

confidence: 99%

PUMA Promotes Bax Translocation by Both Directly Interacting with Bax and by Competitive Binding to Bcl-X_L during UV-induced Apoptosis

Zhang

Xing

Liu

2009

MBoC

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Cell apoptosis induced by UV irradiation is a highly complex process in which different molecular signaling pathways are involved. p53 up-regulated modulator of apoptosis (PUMA) has been proposed as an important regulator in UV irradiation-induced apoptosis. However, the molecular mechanism through which PUMA regulates apoptosis, especially how PUMA activates Bcl-2-associated X protein (Bax) in response to UV irradiation is still controversial. In this study, by using real-time single-cell analysis and fluorescence resonance energy transfer, we investigated the tripartite nexus among PUMA, Bax, and Bcl-X L in living human lung adenocarcinoma cells (ASTC-a-1) to illustrate how PUMA promotes Bax translocation to initiate apoptosis. Our results show that the interaction between PUMA and Bax increased gradually, with Bax translocating to mitochondria and colocalizing with PUMA after UV irradiation, indicating PUMA promotes Bax translocation directly. Simultaneously, the interaction increased markedly between PUMA and Bcl-X L and decreased significantly between Bcl-X L and Bax after UV treatment, suggesting PUMA competitively binds to Bcl-X L to activate Bax indirectly. The above-mentioned results were further confirmed by coimmunoprecipitation experiments. In addition, pifithrin-␣ (a p53 inhibitor) and cycloheximide (a protein synthesis inhibitor) could inhibit PUMA-mediated Bax translocation and cell apoptosis. Together, these studies create an important conclusion that PUMA promotes Bax translocation by both by directly interacting with Bax and by competitive binding to Bcl-X L in UV-induced apoptosis. INTRODUCTIONUV irradiation is a potent carcinogen that can impair cellular functions by directly damaging DNA to induce apoptosis. The cellular response to DNA damage is centered on p53, a transcription factor that exerts its tumor-suppressive function by inducing cell cycle arrest, cell senescence, or apoptosis (Vousden and Lu, 2002). p53 stimulates a wide network of signals to activate the caspases that mediate apoptosis (Strasser et al., 1995). It has been shown that the apoptosis induced by p53 is in large part due to its ability to transcriptionally activate target genes (Chao et al., 2000). Many genes have been identified that are implicated in p53-mediated apoptosis (Vousden and Lu, 2002), such as PUMA and p21. Among the candidate proapoptotic p53 target genes, those that encode mitochondrial proteins such as PUMA stand out because p53-initiated apoptosis seems to proceed through a mitochondrial pathway (Polyak et al., 1997;Li et al., 1999;Soengas et al., 1999;Schuler et al., 2000).p53 up-regulated modulator of apoptosis (PUMA), a member of the Bcl-2 homology (BH)3-only Bcl-2 family proteins, also known as Bcl-2 binding component 3, is a direct transcriptional target of the p53 (Han et al., 2001;Nakano and Vousden, 2001;Yu et al., 2001;Chipuk et al., 2005). PUMA is localized in the mitochondria and induces apoptosis by activating caspases through mitochondrial dysfunction (Nakano and Vousden, 2001;Yu et al., ...

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Apoptosis induced by proteasome inhibition in cancer cells: predominant role of the p53/PUMA pathway

Cited by 98 publications

References 55 publications

The Bcl-2 apoptotic switch in cancer development and therapy

The Bcl-2 apoptotic switch in cancer development and therapy

BCL-2 family regulation by the 20S proteasome inhibitor bortezomib

PUMA Promotes Bax Translocation by Both Directly Interacting with Bax and by Competitive Binding to Bcl-X_L during UV-induced Apoptosis

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Apoptosis induced by proteasome inhibition in cancer cells: predominant role of the p53/PUMA pathway

Cited by 98 publications

References 55 publications

The Bcl-2 apoptotic switch in cancer development and therapy

The Bcl-2 apoptotic switch in cancer development and therapy

BCL-2 family regulation by the 20S proteasome inhibitor bortezomib

PUMA Promotes Bax Translocation by Both Directly Interacting with Bax and by Competitive Binding to Bcl-XL during UV-induced Apoptosis

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PUMA Promotes Bax Translocation by Both Directly Interacting with Bax and by Competitive Binding to Bcl-X_L during UV-induced Apoptosis