Regulation and targeting of antiapoptotic XIAP in acute myeloid leukemia

Carter, Bing Z.; Milella, Michèle; Tsao, Twee; McQueen, Teresa; Schober, Wendy; Hu, Wei; Dean, Nicholas M.; Steelman, Linda S.; McCubrey, James A.; Andreeff, Michael

doi:10.1038/sj.leu.2403113

Cited by 109 publications

(101 citation statements)

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“…Antisense XIAP has been shown to induce apoptosis and to sensitize primary acute myeloid leukemia blasts to chemotherapy. 83 Antagonizing Survivin by antisense approaches also showed promising results both in vitro by apoptosis-induction in leukemia and lymphoma cells 99,137 and in vivo by reducing lymphoma development and growth in murine xenograft models. 137,138 Furthermore, the cancer-specific expression of Survivin has elicited studies investigating the therapeutic use of siRNA and dominantnegative mutant Survivin to antagonize Survivin function.…”

Section: Iaps As Targets For Cancer Therapymentioning

confidence: 99%

“…131 In leukemia, c-IAP1, c-IAP2, XIAP and Survivin expression is associated with the PI-3K/Akt pathway and therapy resistance. 83,103,132 Furthermore, transformation of myeloid cells is accompanied by PI-3K/Akt-mediated induction of NF-kB and c-IAP2. 133 …”

Section: Figurementioning

confidence: 99%

“…82,83 IAPs and cancer Acquired resistance to apoptosis is a hallmark of most types of cancer 84,85 as it provides the opportunity for malignant cells to escape cellular checkpoints that detect abnormalities within the cell or its direct surroundings. Furthermore, deregulated apoptosis pathways are critically involved in therapy resistance of many tumors, since chemo-and radiotherapy largely depend on the induction of apoptosis.…”

Section: Figurementioning

confidence: 99%

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Inhibitor of apoptosis proteins: new therapeutic targets in hematological cancer?

Graaf

Witte²,

Jansen

2004

Leukemia

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Apoptosis is an essential process for the selection and survival of lymphocytes. Resistance to apoptosis can promote malignant transformation of hematopoietic cells. Proteins that regulate apoptosis may therefore be critically involved in the development of hematological cancer. A delicate balance between pro-and antiapoptotic mechanisms determines whether a cell death signal can activate the execution of the apoptotic cell death program. The family of inhibitor of apoptosis (IAP) proteins is a recently identified, novel category of apoptosis-regulatory proteins. IAPs can inhibit the activation of caspases that are the executioners of apoptosis, activated by both the extrinsic and intrinsic pathway. IAPs may thereby set the threshold for apoptosis-activation and play a key role in the regulation of apoptotic cell death. IAPs themselves are also subject to strict regulation through feedback mechanisms. This paper focuses on the role of IAP family proteins in the regulation of apoptosis and discusses implications for their involvement in cancer and possible use for cancer therapy, especially in leukemias and lymphomas.

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Section: Iaps As Targets For Cancer Therapymentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

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Inhibitor of apoptosis proteins: new therapeutic targets in hematological cancer?

Graaf

Witte²,

Jansen

2004

Leukemia

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“…Moreover, ERK can translocate to the nucleus and phosphorylate additional transcription factors such as Elk1, CREB and Fos which bind promoters of many genes, including growth factor and cytokine genes important in stimulating the growth and survival of multiple cell types including breast cells (Deng et al, 1994, Wang et al, 1994, Davis., 1995, Thomas et al, 1997, Robinson et al, 1998, McCubrey et al, 2000, Aplin et al, 2001, Tresini et al, 2001, Eblen et al, 2001, Adachi et al, 2002, Ponti et al, 2002, Fry et al, 2002. The Raf/MEK/ERK pathway can also modulate the activity of many proteins involved in apoptosis including: Bcl-2, Bad, Bim, myeloid cell leukemia-1 (Mcl-1), caspase 9, and survivin , Carter et al, 2003, Jia et al, 2003, Troppmair et al, 2003, Domina et al, 2004, Harada et al, 2004, Marani et al, 2004, Gelinas et al, 2006.…”

Section: Overview Of the Pi3k/pten/akt/mtor And Raf/mek/erk Pathways mentioning

confidence: 99%

Alteration of Akt activity increases chemotherapeutic drug and hormonal resistance in breast cancer yet confers an achilles heel by sensitization to targeted therapy

McCubrey

Sokolosky

Lehmann

et al. 2008

Advances in Enzyme Regulation

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The PI3K/PTEN/Akt/mTOR pathway plays critical roles in the regulation of cell growth. The effects of this pathway on drug resistance and cellular senescence of breast cancer cells has been a focus of our laboratory. Introduction of activated Akt or mutant PTEN constructs which lack lipid phosphatase [PTEN(G129E)] or lipid and protein phosphatase [PTEN(C124S)] activity increased the resistance of the cells to the chemotherapeutic drug doxorubicin, and the hormonal drug tamoxifen. Activated Akt and PTEN genes also inhibited the induction of senescence after doxorubicin treatment; a phenomenon associated with unrestrained proliferation and tumorigenesis. Interference with the lipid phosphatase domain of PTEN was sufficient to activate Akt/mTOR/p70S6K as MCF-7 cells transfected with the mutant PTEN gene lacking the lipid phosphatase activity [PTEN(G129E)] displayed elevated levels of activated Akt and p70S6K compared to empty vector transfected cells. Cells transfected with mutant PTEN or Akt constructs were hypersensitive to mTOR inhibitors when compared with the parental or empty vector transfected cells. Akt-transfected cells were cultured for over two months in tamoxifen from which tamoxifen and doxorubicin resistant cells were isolated that were >10-fold more resistant to tamoxifen and doxorubicin than the original Akt-transfected cells. These cells had a decreased induction of both activated p53 and total p21 Cip1 upon doxorubicin treatment. Furthermore, these cells had an increased inactivation of GSK-3β and decreased expression of the estrogen receptor-α. In these drug resistant cells, there was an increased activation Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errorsmaybe discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. of ERK which is associated with proliferation. These drug resistant cells were hypersensitive to mTOR inhibitors and also sensitive to MEK inhibitors, indicating that the enhanced p70S6K and ERK expression was relevant to their drug and hormonal resistance. Given that Akt is overexpressed in greater than 50% of breast cancers, our results point to potential therapeutic targets, mTOR and MEK. These studies indicate that activation of the Akt kinase or disruption of the normal activity of the PTEN phosphatase can have dramatic effects on activity of p70S6K and other downstream substrates and thereby altering the therapeutic sensitivity of breast cancer cells. The effects of doxorubicin and tamoxifen on induction of the Raf/MEK/ERK and PI3K/Akt survival pathways were examined in unmodified MCF-7 breast cells. Doxorubicin was a potent inducer of activated ERK and to a lesser extent Akt. Tamoxifen also in...

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“…[26][27][28][29][30][31][32][33][34][35][36][37] The Raf/MEK/ERK pathway can also modulate the activity of many proteins involved in apoptosis including: B cell leukemia-2 (Bcl-2), Bad, Bim, myeloid cell leukemia-1 (Mcl-1), caspase 9 and survivin. [38][39][40][41][42][43][44][45][46][47] Raf-1 has many roles that are independent of MEK and ERK. It is important to discuss these interactions as they serve to illustrate the concept that targeting Raf, which will be covered in the accompanying review, will have additional effects than just inhibition of downstream MEK/ERK.…”

Section: Overview Of the Ras/raf/mek/erk Pathwaymentioning

confidence: 99%

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

et al. 2008

Self Cite

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Mutations and chromosomal translocations occur in leukemic cells that result in elevated expression or constitutive activation of various growth factor receptors and downstream kinases. The Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways are often activated by mutations in upstream genes. The Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways are regulated by upstream Ras that is frequently mutated in human cancer. Recently, it has been observed that the FLT-3 and Jak kinases and the phosphatase and tensin homologue deleted on chromosome 10 ( PTEN) phosphatase are also frequently mutated or their expression is altered in certain hematopoietic neoplasms. Many of the events elicited by the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways have direct effects on survival pathways. Aberrant regulation of the survival pathways can contribute to uncontrolled cell growth and lead to leukemia. In this review, we describe the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT signaling cascades and summarize recent data regarding the regulation and mutation status of these pathways and their involvement in leukemia

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Regulation and targeting of antiapoptotic XIAP in acute myeloid leukemia

Cited by 109 publications

References 50 publications

Inhibitor of apoptosis proteins: new therapeutic targets in hematological cancer?

Inhibitor of apoptosis proteins: new therapeutic targets in hematological cancer?

Alteration of Akt activity increases chemotherapeutic drug and hormonal resistance in breast cancer yet confers an achilles heel by sensitization to targeted therapy

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

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