Molecular mechanisms of nutlin-induced apoptosis in multiple myeloma

Saha, Manujendra N.; Jiang, Hua; Chang, Hong

doi:10.4161/cbt.10.6.12535

Cited by 51 publications

(36 citation statements)

References 52 publications

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“…As shown in Fig 2A and Fig S1, PUMA expression was significantly decreased in MM1R cells as compared with MM1S cells. In agreement with the wild type status of p53 in these two cell lines (21), equal levels of p53 protein were detected by immunoblots. To further verify that PUMA plays a major role in promoting Dex resistance in MM1R cells, we lentivirally transduced MM1R cells with vectors expressing dsRed protein alone as control (V-dsRed) or dsRed in combination with PUMA (V- PUMA -dsRed).…”

Section: Resultssupporting

confidence: 79%

Targeting the miR-221–222/PUMA/BAK/BAX Pathway Abrogates Dexamethasone Resistance in Multiple Myeloma

Zhao

Chu

et al. 2015

Cancer Research

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Despite recent therapeutic advances that have doubled the median survival time of patients with multiple myeloma (MM), intratumor genetic heterogeneity contributes to disease progression and emergence of drug resistance. MicroRNAs (miRs), are noncoding small RNAs that play important roles in the regulation of gene expression, and have been implicated in cancer progression and drug resistance. We investigated the role of the miR-221-222 family in dexamethasone(Dex)-induced drug resistance in MM using the isogenic cell lines, MM1R and MM1S, which represent models of resistance and sensitivity, respectively. Analysis of array comparative genome hybridization (aCGH) data revealed gain of chromosome X regions at band p11.3, wherein the miR-221-222 resides, in resistant MM1R cells but not in sensitive MM1S cells. DNA copy number gains in MM1R cells were associated with increased miR-221-222 expression and downregulation of p53-upregulated modulator of apoptosis (PUMA) as a likely pro-apoptotic target. We confirmed PUMA mRNA as a direct target of miR-221-222 in MM1S and MM1R cells by both gain- and loss- of function studies. In addition, miR-221-222 treatment rendered MM1S cells resistant to Dex, whereas anti-miR-221-222 partially restored the Dex sensitivity of MM1R cells. These studies have uncovered a role for miR-221-222 in MM drug resistance, and suggest a potential therapeutic role for inhibitors of miR-221-222 binding to PUMA mRNA as a means of overcoming Dex resistance in patients. The clinical utility of this approach is predicated on the ability of anti-sense miR-221-222 to increase survival while reducing tumor burden, and is strongly supported by the metastatic propensity of MM1R cells in preclinical mouse xenograft models of MM. Moreover, our observation of increased levels of miR-221-222 with decreased PUMA expression in MM cells from patients at relapse versus untreated controls suggests an even broader role for miR-221-222 in drug resistance, and provides a rationale for the targeting of miR-221-222 as a means of improving patient outcomes.

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Section: Resultssupporting

confidence: 79%

Targeting the miR-221–222/PUMA/BAK/BAX Pathway Abrogates Dexamethasone Resistance in Multiple Myeloma

Zhao

Chu

et al. 2015

Cancer Research

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“…We and others have demonstrated potent anti-myeloma activity of nutlin by molecular and functional analysis of the p53 pathway in MM cell lines, primary MM patient samples and in the cells of the bone marrow microenvironment [63-65]. We explored the molecular mechanisms for nutlin-induced apoptosis in MM cells and provided the evidence for association of both p53-transcription-dependent and -independent pathways (Figure 1A) [65].…”

Section: Introductionmentioning

confidence: 99%

Targeting p53 by small molecules in hematological malignancies

2013

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Abstractp53 is a powerful tumor suppressor and is an attractive cancer therapeutic target. A breakthrough in cancer research came from the discovery of the drugs which are capable of reactivating p53 function. Most anti-cancer agents, from traditional chemo-and radiation therapies to more recently developed non-peptide small molecules exert their effects by enhancing the anti-proliferative activities of p53. Small molecules such as nutlin, RITA, and PRIMA-1 that can activate p53 have shown their anti-tumor effects in different types of hematological malignancies. Importantly, nutlin and PRIMA-1 have successfully reached the stage of phase I/II clinical trials in at least one type of hematological cancer. Thus, the pharmacological activation of p53 by these small molecules has a major clinical impact on prognostic use and targeted drug design. In the current review, we present the recent achievements in p53 research using small molecules in hematological malignancies. Anticancer activity of different classes of compounds targeting the p53 signaling pathway and their mechanism of action are discussed. In addition, we discuss how p53 tumor suppressor protein holds promise as a drug target for recent and future novel therapies in these diseases.

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“…As a nuclear transcription factor, p53 has the capability to activate or suppress the expression a large number of genes such as p21, Bax, p53INP1, Bid and Puma (Megyeri, et al 2007; Skirnisdottir and Seidal 2012; Zhou, et al 2012). Some evidences have suggested that p53 also has a non-transcriptional function with a direct role at mitochondria in promoting apoptosis (Saha, et al 2010), suggesting that p53 is one of the most important proteins during podocyte apoptosis. In the present study, nuclear p53 can be upregulated in podocytes treated by Ang II, and the apoptotic podocytes reveal a simultaneous increase.…”

Section: Discussionmentioning

confidence: 99%

c-Abl mediates angiotensin II-induced apoptosis in podocytes

et al. 2013

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Backgroud Angiotensin II (Ang II) has been reported to cause podocyte apoptosis in rats both in vivo and in vitro studies. However, the underlying mechanisms are poorly understood. In the present study, we investigated the role of the nonreceptor tyrosine kinase c-Abl in Ang II-induced podocyte apoptosis. Methods Male Sprague-Dawley rats in groups of 12 were administered either Ang II (400 kg-1·kg-1·min-1) or Ang II + STI-571 (50 mg·kg-1·d-1) by osmotic minipumps. In addition, 12 rats-receiving normal saline served as the control. Glomeruli c-Abl expression was carried out by real time PCR, Western blotting and immunolabeled, and occurrence of apoptosis was carried out by TUNEL staining and transmission electron microscopic analysis. In vitro studies, conditionally immortalized mouse podocytes were treated with Ang II (10-9-10-6 M) in the presence or absence of either c-Abl inhibitor, Src-I1, specific c-Abl siRNA, or c-Abl plasmid alone. Quantification of podocyte c-Abl expression and c-Abl phosphorylation at Y245 and Y412 was carried out by real time PCR, Western blotting and immunofluorescence imaging. The nuclear c-Abl and p53 were quantified by co-immunoprecipitation and Western blotting studies. Podocyte apoptosis was analysed by flow cytometry and Hoechst-33342 staining. Results c-Abl expression was demonstrated in rat kidney podocytes in vivo and cultured mouse podocytes in vitro. Ang II-receiving rats displayed enhanced podocyte c-Abl expression. And Ang II significantly stimulated c-Abl expression in cultured podocytes. Furthermore Ang II upregulated podocyte c-Abl phosphorylation at Y245 and Y412. Ang II also induced an increase of nuclear p53 protein and nuclear c-Abl-p53 complexes in podocytes and podocyte apoptosis. Down-regulation of c-Abl expression by c-Abl inhibitor (Src-I1) as well as specific siRNA inhibited Ang II-induced podocyte apoptosis; conversely, podoctyes transfected with c-Abl plasmid displayed enhanced apoptosis. Conclusions These findings indicate that c-Abl may mediates Ang II-induced podocyte apoptosis, and inhibition of c-Abl expression can protect podocytes from Ang II-induced injury.

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Molecular mechanisms of nutlin-induced apoptosis in multiple myeloma

Cited by 51 publications

References 52 publications

Targeting the miR-221–222/PUMA/BAK/BAX Pathway Abrogates Dexamethasone Resistance in Multiple Myeloma

Targeting the miR-221–222/PUMA/BAK/BAX Pathway Abrogates Dexamethasone Resistance in Multiple Myeloma

Targeting p53 by small molecules in hematological malignancies

c-Abl mediates angiotensin II-induced apoptosis in podocytes

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