FOXO1 is a tumor suppressor in classical Hodgkin lymphoma

Xie, Linka; Ushmorov, Alexey; Leithäuser, Frank; Guan, Hanfeng; Steidl, Christian; Färbinger, Johanna; Pelzer, Christin; Vogel, Michael; Maier, Harald J.; Gascoyne, Randy D.; Möller, Peter; Wirth, Thomas

doi:10.1182/blood-2011-09-381905

Cited by 152 publications

(169 citation statements)

References 46 publications

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“…62 The tumor suppressor FOXO1, which is inactivated by AKT, is repressed in HRS cells; only one of 32 cases analyzed by Xie et al was FOXO1 positive. 63 Inhibition of AKT caused a dose-dependent increase in FOXO1 expression in classic HL cell lines. 63 Together, these findings emphasize the important role of PI3K in hematologic malignancies and suggest that inhibition of this pathway may be a viable therapeutic approach.…”

Section: Mantle Cell Lymphomamentioning

confidence: 99%

“…63 Inhibition of AKT caused a dose-dependent increase in FOXO1 expression in classic HL cell lines. 63 Together, these findings emphasize the important role of PI3K in hematologic malignancies and suggest that inhibition of this pathway may be a viable therapeutic approach. Further investigation of PI3K inhibitors in hematologic malignancies may help to establish the role of this drug class in the treatment armamentarium and improve patient outcomes.…”

Section: Mantle Cell Lymphomamentioning

confidence: 99%

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Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies

et al. 2014

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The phosphoinositide 3-kinase pathway represents an important anticancer target because it has been implicated in cancer cell growth, survival, and motility. Recent studies show that PI3K may also play a role in the development of resistance to currently available therapies. In a broad range of cancers, various components of the phosphoinositide 3-kinase signaling axis are genetically modified, and the pathway can be activated through many different mechanisms. The frequency of genetic alterations in the phosphoinositide 3-kinase pathway, coupled with the impact in oncogenesis and disease progression, make this signaling axis an attractive target in anticancer therapy. A better understanding of the critical function of the phosphoinositide 3-kinase pathway in leukemias and lymphomas has led to the clinical evaluation of novel rationally designed inhibitors in this setting. Three main categories of phosphoinositide 3-kinase inhibitors have been developed so far: agents that target phosphoinositide 3-kinase and mammalian target of rapamycin (dual inhibitors), pan-phosphoinositide 3-kinase inhibitors that target all class I isoforms, and isoform-specific inhibitors that selectively target the α, -β, -g, or -d isoforms. Emerging data highlight the promise of phosphoinositide 3-kinase inhibitors in combination with other therapies for the treatment of patients with hematologic malignancies. Further evaluation of phosphoinositide 3-kinase inhibitors in first-line or subsequent regimens may improve clinical outcomes. This article reviews the role of phosphoinositide 3-kinase signaling in hematologic malignancies and the potential clinical utility of inhibitors that target this pathway. ABSTRACTE. Jabbour et al. 8 haematologica | 2014; 99 (1) where it activates the AKT serine/threonine kinase by phosphorylating the threonine 308 residue (Figure 1). In turn, AKT phosphorylates many downstream substrates, including forkhead box protein O (FOXO), glycogen synthase kinase-3 (GSK-3), and Bcl-2 associated death promoter (BAD). AKT-mediated phosphorylation also inhibits the proline-rich AKT substrate of 40 kDa (PRAS40) and tuberous sclerosis complex 2 (TSC2), thereby activating mTOR complex 1 (mTORC1). mTORC1 consists of mTOR, mTOR-associated protein LST8 homolog (mLST8), regulatory associated protein of mTOR (RAPTOR), DEP domain TOR-binding protein (DEPTOR), and PRAS40. Activated mTORC1 stimulates protein synthesis by phosphorylating the ribosomal kinase proteins S6K1 (p70S6K/p85S6K) and S6K2 (p54S6K), and the eukaryotic initiation factor 4E-binding proteins (4E-BP1, 4E-BP2, and 4E-BP3). 17,18 mTORC2 is physiologically distinct from mTORC1 and consists of mTOR, mLST8, DEPTOR, rapamycin-insensitive companion of mTOR (RICTOR), protein observed with RIC-TOR (PROTOR), and mammalian stress-activated protein kinase interaction protein 1 (mSIN1). Unlike mTORC1, mTORC2 is considered rapamycin-insensitive because its inhibition requires prolonged drug exposure. While its function is not fully elucidated, mTORC2 is known to phosphoryla...

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Section: Mantle Cell Lymphomamentioning

confidence: 99%

Section: Mantle Cell Lymphomamentioning

confidence: 99%

Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies

et al. 2014

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“…In view of the fact that, in our mouse model, expression of Tg myristoylated Akt1 (Akt1 Tg) in T and B cells did not lead to B-cell expansion [18] and that enhanced Akt signaling is linked to autoimmunity and generation of tumors [19,20], we assessed the effects of constitutive Akt1 signals on B-cell function and development. We found a reduced BCR-induced proliferation of splenic B cells from Akt1 Tg mice, which correlated with reduced activation of several signaling cascades.…”

Section: Introductionmentioning

confidence: 99%

Constitutive Akt1 signals attenuate B‐cell receptor signaling and proliferation, but enhance B‐cell migration and effector function

Pierau

Simma

et al. 2012

Eur J Immunol

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Ligation of the BCR induces a complex signaling network that involves activation ofAkt, a family of serine/threonine protein kinases associated with B-cell development, proliferation, and tumor formation. Here, we analyzed the effect of enhanced Akt1 signals on B-cell maturation and function. Unexpectedly, we found that peripheral B cells overexpressing Akt1 were less responsive to BCR stimuli. This correlated with a decrease in Ca 2+ -mobilization and proliferation, in an impaired activation of Erk1/2 and mammalian target of rapamycin (mTOR) kinases and poor mobilization of NFATc1 and NF-κB/p65 factors. In contrast, activation of STAT5 and migration of B cells toward the chemokine SDF1α was found to be enhanced. Akt1 Tg mice showed an altered maturation of peritoneal and splenic B1 B cells and an enhanced production of IgG1 and IgG3 upon immunization with the T-cell independent Ag TNP-Ficoll. Furthermore, mice homozygous for Tg Akt1 showed a severe block in the maturation of B-cell precursors in BM and a strong enrichment of plasma cells in spleen. Altogether, our data reveal that enhanced Akt1 signals modify BCR signaling strength and, thereby, B-cell development and effector function.Keywords: B cell r NFAT r PKB/Akt r SDF1α r STAT5 IntroductionIn the BM B-cell progenitors develop through defined stages of differentiation to immature B cells giving rise to follicular B2 (FO) B cells, marginal zone (MZ), and B1 B cells. These processes are controlled by the signal intensity arising from the pre-BCR or mature BCR, which activate similar sets of signaling molecules. The most proximal signaling events upon BCR ligation include Correspondence: Prof. Ursula H. Bommhardt e-mail: ursula.bommhardt@med.ovgu.de activation of the protein tyrosine kinases Lyn and Syk. A prominent substrate of Syk is the adaptor protein SLP65/BLNK, which recruits Bruton's tyrosine kinase, phospholipase Cγ2, and further signal proteins into supramolecular complexes that trigger the activation of multiple signaling pathways. Activated phospholipase Cγ2 cleaves the membrane lipid phosphatidylinositol-4, 5-bisphosphate (PIP2) to generate diacylglycerol and inositol-1,4,5-trisphosphate (IP3), two second messengers affecting the * These authors contributed equally to this work. Eur. J. Immunol. 2012. 42: 3381-3393 activation of PKC family members, MAPK activation, and the release of Ca 2+ from intracellular stores, which finally leads to influx of extracellular Ca 2+ . Elevated intracellular Ca 2+ -levels induce the activity of serine/threonine-specific phosphatase calcineurin and, in turn, a set of Ca 2+ -regulated transcription factors, in particular of NFAT and NF-κB factors that control various gene expression programs [1].An important signaling cascade induced after BCR engagement encompasses the lipid kinase family of class I PI3Ks [2][3][4]. Mature peripheral B cells lacking a BCR could be rescued from apoptosis by the ectopic expression of a constitutively active catalytic subunit of PI3K, indicating that PI3K signals support the surv...

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“…Given the critical role for the Akt/FOXO1 axis in the regulation of cell survival (Rena et al, 1999;Xie et al, 2012), we examined the effect of miR-9 overexpression on Akt and FOXO1 phosphorylation in ovarian cancer cells. Western blot analysis showed that the phosphorylation levels of Akt and FOXO1 were significantly (p<0.05) lower in miR-9-overexpressing SKOV3 cells than in those transfected with control oligonucleotides ( Figure 4).…”

Section: Mir-9 Overexpression Inhibits Akt Activation and Foxo1 Phospmentioning

confidence: 99%

“…Phosphorylation and inactivation of forkhead box protein O1 (FOXO1) is an important mechanism by which Akt activation promotes cell survival (Rena et al, 1999). FOXO1 acts as a tumor suppressor in a variety of cancers including ovarian cancer (Goto et al, 2008;Xie et al, 2012). Several studies have demonstrated that the anticancer effect of curcumin is associated with the modulation of FOXO1 expression (Li et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Induction of MicroRNA-9 Mediates Cytotoxicity of Curcumin Against SKOV3 Ovarian Cancer Cells

Zhao¹,

Zhang²,

Zhang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Background: Curcumin, a phenolic compound extracted from the rhizomes of Curcuma longa, has shown cytotoxic effects against a variety of cancers. The aim of this study was to identify potential microRNA (miRNA) mediators of the anticancer effects of curcumin in ovarian cancer cells. Materials and Methods: SKOV3 ovarian cancer cells were treated with curcumin (10-60 μM) and miR-9 expression, cell proliferation, and apoptosis were assessed. The effects of miR-9 depletion on curcumin-mediated growth suppression were also examined. Phosphorylation of Akt and forkhead box protein O1 (FOXO1) was measured in cells with miR-9 overexpression or curcumin treatment. Results: Curcumin caused a significant and dose-dependent increase of miR-9 expression in SKOV3 cells, while significantly impeding cell proliferation and stimulating apoptosis. Depletion of miR-9 significantly (p<0.05) attenuated the growth-suppressive effects of curcumin on SKOV3 cells, coupled with reduced percentages of apoptotic cells. In contrast, overexpression of miR-9 significantly enhanced the cleavage of caspase-3 and poly(ADP-ribose) polymerase and promoted apoptotic death in SKOV3 cells. Western blot analysis showed that both miR-9 overexpression and curcumin similarly caused a significant (p<0.05) decline in the phosphorylation of Akt and FOXO1, compared to untreated cells. Conclusions: The present study provided evidence that curcumin exerts its cytotoxic effects against SKOV3 ovarian cancer cells largely through upregulation of miR-9 and subsequent modulation of Akt/FOXO1 axis. Further studies are needed to identify direct targets of miR-9 that mediate the anticancer effects of curcumin in ovarian cancer cells.

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FOXO1 is a tumor suppressor in classical Hodgkin lymphoma

Cited by 152 publications

References 46 publications

Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies

Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies

Constitutive Akt1 signals attenuate B‐cell receptor signaling and proliferation, but enhance B‐cell migration and effector function

Induction of MicroRNA-9 Mediates Cytotoxicity of Curcumin Against SKOV3 Ovarian Cancer Cells

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