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Journal Article•DOI•

Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia.

Naoto Morishita1, Hirokazu Tsukahara1, Kosuke Chayama, Toshiaki Ishida2, Kana Washio1, Takako Miyamura1, Nobuko Yamashita1, Megumi Oda1, Tsuneo Morishima1 •
Okayama University1, Boston Children's Hospital2
15 Jul 2012-Pediatric Blood & Cancer (Pediatr Blood Cancer)-Vol. 59, Iss: 1, pp 83-89
TL;DR: This study was undertaken to explore the clinical relevance and molecular mechanisms underlying the activation of Akt (i.e., phosphorylated Akt, P‐Akt) in pediatric B‐pre ALL.
Abstract: Background Activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, a pro-survival pathway, plays important roles in tumor cell growth. However, the role of Akt in the pathogenesis of pediatric B-precursor acute lymphoblastic leukemia (B-pre ALL) remains to be clarified. This study was undertaken to explore the clinical relevance and molecular mechanisms underlying the activation of Akt (i.e., phosphorylated Akt, P-Akt) in pediatric B-pre ALL. Procedure We evaluated the activation status of Akt in bone marrow samples from 21 children with newly diagnosed B-pre ALL and correlated the expression level of P-Akt with clinicopathologic and prognostic features. Additionally, we transfected the myristoylated Akt cDNA into the B-pre ALL cell line, Nalm-6, and examined the effect, in vitro, of Akt activation on the response to antitumor drugs. Results P-Akt expression in B-pre ALL blast cells at diagnosis was associated significantly with poor response to induction chemotherapy including prednisolone, dexamethasone, vincristine, and adriamycin in B-pre ALL patients. Both overall survival and relapse-free survival in patients with P-Akt expression were reduced significantly more than in patients without P-Akt expression. Activation of Akt reduced the extent of apoptosis induced by the antitumor drugs in Nalm-6 listed above. Activation of Akt did not induce expression of P-glycoprotein, a drug transporter that is capable of conferring multidrug resistance. Conclusion These results support the contention that Akt activation is a mechanism of chemotherapeutic resistance in B-pre ALL and suggest that Akt can be a therapeutic target for the treatment of relapsed or refractory pediatric B-pre ALL. Pediatr Blood Cancer 2012; 59: 83–89. © 2011 Wiley Periodicals, Inc.

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氏 名
授 与 し た 学 位
専 攻 分 野 の名 称
学 位 授 与 番 号
学 位 授 与 の 日付
学 位 授 与 の 要 件
学 位 論 文 題 目
森 下 直 人
博 士
医 学
博 甲第 4468 号
平成 24年 3月 2 3 日
医歯薬学総合研究科病態制御科学専攻
(学位 規則 第 4条 第 1項該 当)
ActivationofAktisAssociatedWithPoorPrognosis
and Chemotherapeutic Resistance in Pediatric
B‑PrecursorAcuteLymphoblasticLeukemia
(Akt
の活性化は､小児のB前駆細胞性急性 リンパ性 白血病に
おける予後不良と化学療法抵抗性に関連 している)
論 文 審 査 委 員
教授 谷 本 光音 教授 岩 月 啓 氏 教 授 杉 山 育
学 位 論 文 内 容 の 要 旨
pt3Kl
触 経路壮生存促進性の経路であり､リン酸化によるjkt浄財 ヒは腰痛細胞の成長におい
て重要な役割を果たしている｡しかし､小児
B前納 包性急性リンパ性白血病 (以下､RpreJqL)
の樹散生理におけるjgdの役割はいまだ不明の部分が多Llo今回､我々R 小児BpreAu.にお
けるj
kt活性化が臨床検査学的に分袖 壁学的にどのような意義を有するのか調べた｡
21名の小児 BpreAL患者を対象に行った飽和 勺検討では 骨髄倹体でjgd:が括性化している
患者では菅性化していない患者i3ヒべて化学馳 こ対する反応性が有意に乏しく､生命予後も有
意に悪いことが示 された
CIn trarBfectionによりAktを持続 的に活性化させたBpreA⊥細胞
株 恥 Im6細骨砂 を用いた基砲的検討では､抗脚 Jにより誘導されるアポ トーシスが有意に抑
制されることが示 された｡以上の結果より､
Bpre凡Lにおいて､jgdl措性化樹 臓 超抗性を
もたらす機構
の 1つであり､Jqdが†㈱ こ抵抗性を示 机 ＼児Bpre,qLL患都 こおいて治療標的
になりえることが示唆された｡
論 文 審 査 結 果 の 要 旨
本研究では､′J､児 B･preALLにおいて､骨髄検体で Aktが活性化 している患者 と活性
化が明らかでない患者 との予後を比較 した結果､
Aktの活性化が生存 とかかわっているこ
とを見出 した｡予後に影響を与える機構を解明するため
､B･preALL細胞株であるNalm‑6
株に活性化 した Akt遺伝子をせん孔法で導入 した細胞株に於いては､化学療法剤である
ステロイ ド､オンコビン､ア ドリアマイシン添加によるアポ トーシスが明 らかに抑制 され
ていることを見出 した｡この結果は､A
kt遺伝子の活性化経路がアポ トーシス抑制を介 し
て化学療法治療に対する抵抗性を獲得 していることを示 した新たな知見である｡
よって､本研究者は博士 (医学)の学位を得る資格があると認める｡
Citations
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Journal Article•DOI•
Is There A Causal Relationship between Childhood Obesity and Acute Lymphoblastic Leukemia? A Review

[...]

Molly J Dushnicky1, Samina Nazarali2, Samina Nazarali1, Adhora Mir2, Adhora Mir1, Carol Portwine1, Carol Portwine2, Muder Constantine Samaan •
McMaster University1, McMaster Children's Hospital2
22 Oct 2020-Cancers
TL;DR: Critical questions persist as to whether the adipose tissue microenvironment and endocrine actions can play a causal role in childhood ALL, and there is a need for more research to address these questions.
Abstract: Childhood obesity is a growing epidemic with numerous global health implications. Over the past few years, novel insights have emerged about the contribution of adult obesity to cancer risk, but the evidence base is far more limited in children. While pediatric patients with acute lymphoblastic leukemia (ALL) are at risk of obesity, it is unclear if there are potential causal mechanisms by which obesity leads to ALL development. This review explores the endocrine, metabolic and immune dysregulation triggered by obesity and its potential role in pediatric ALL's genesis. We describe possible mechanisms, including adipose tissue attraction and protection of lymphoblasts, and their impact on ALL chemotherapies' pharmacokinetics. We also explore the potential contribution of cytokines, growth factors, natural killer cells and adipose stem cells to ALL initiation and propagation. While there are no current definite causal links between obesity and ALL, critical questions persist as to whether the adipose tissue microenvironment and endocrine actions can play a causal role in childhood ALL, and there is a need for more research to address these questions.

10 citations

Original Article Expression of NF-κB and PTEN in primary epithelial ovarian carcinoma and the correlation with chemoresistance

[...]

Lili Wang, Chenxu Wang, Shanshan Jin, Donghui Qu, Huanchun Ying 
01 Jan 2015
TL;DR: In this article, the authors investigated the relationship of NF-κB p65 and PTEN protein with chemotherapy resistance in ovarian cancer by measuring their expression in primary epithelial ovarian cancer, and to explore the correlation of the expression of these two proteins with ovarian carcinoma and their clinical significance.
Abstract: The present study aims to investigate the relationship of NF-κB p65 and PTEN protein with chemotherapy resistance in ovarian cancer by measuring their expression in primary epithelial ovarian cancer, and to explore the correlation of the expression of these two proteins with ovarian carcinoma and their clinical significance. Ovarian cancer patients (n = 161) were divided into two groups: sensitive group (n = 82) and resistant group (n = 79). Ex- pression of NF-κB p65 and PTEN protein in the ovarian cancer tissues was determined using immunohistochemistry to assess the relationship and correlation between the expression levels of these two proteins and chemotherapy resistance of ovarian carcinoma. The Cox model was used to analyze the independent risk factors associated with ovarian cancer prognosis. The expression of NF-κB p65 in the sensitive group (68.29%) was lower than that of the resistant group (94.94%). In contrast, the expression of PTEN protein in the sensitive group (50.00%) was higher than that of the resistant group (17.72%). Expression of NF-κB p65 was negatively correlated with that of PTEN pro- tein in ovarian cancer tissue (rs = -0.246, P = 0.002). Expression of NF-κB p65 or PTEN protein and surgical stage of ovarian cancer were independent risk factors associated with chemoresistance (all P < 0.05). Low expression of PTEN and high expression of NF-κB are significant risk factors for chemotherapy resistance of ovarian cancer patients.

9 citations

Journal Article•DOI•
Combined Application of Pan-AKT Inhibitor MK-2206 and BCL-2 Antagonist Venetoclax in B-Cell Precursor Acute Lymphoblastic Leukemia.

[...]

Anna Richter1, Elisabeth Fischer1, Clemens Holz1, Julia Schulze1, Sandra Lange1, Anett Sekora1, Gudrun Knuebel1, Larissa Henze1, Catrin Roolf1, Hugo Murua Escobar1, Christian Junghanss1 •
University of Rostock1
09 Mar 2021-International Journal of Molecular Sciences
TL;DR: In this paper, the effect of pan-AKTK/AKT inhibitors on B-ALL cell lines and primary samples and investigate potential synergistic effects with BCL-2 inhibitor venetoclax to overcome limitations in apoptosis induction.
Abstract: Aberrant PI3K/AKT signaling is a hallmark of acute B-lymphoblastic leukemia (B-ALL) resulting in increased tumor cell proliferation and apoptosis deficiency. While previous AKT inhibitors struggled with selectivity, MK-2206 promises meticulous pan-AKT targeting with proven anti-tumor activity. We herein, characterize the effect of MK-2206 on B-ALL cell lines and primary samples and investigate potential synergistic effects with BCL-2 inhibitor venetoclax to overcome limitations in apoptosis induction. MK-2206 incubation reduced AKT phosphorylation and influenced downstream signaling activity. Interestingly, after MK-2206 mono application tumor cell proliferation and metabolic activity were diminished significantly independently of basal AKT phosphorylation. Morphological changes but no induction of apoptosis was detected in the observed cell lines. In contrast, primary samples cultivated in a protective microenvironment showed a decrease in vital cells. Combined MK-2206 and venetoclax incubation resulted in partially synergistic anti-proliferative effects independently of application sequence in SEM and RS4;11 cell lines. Venetoclax-mediated apoptosis was not intensified by addition of MK-2206. Functional assessment of BCL-2 inhibition via Bax translocation assay revealed slightly increased pro-apoptotic signaling after combined MK-2206 and venetoclax incubation. In summary, we demonstrate that the pan-AKT inhibitor MK-2206 potently blocks B-ALL cell proliferation and for the first time characterize the synergistic effect of combined MK-2206 and venetoclax treatment in B-ALL.

8 citations

Journal Article•DOI•
New biomarkers and therapeutic strategies in acute lymphoblastic leukemias: Recent advances

[...]

Carolina Simioni1, Fabio Bergamini1, Martina Ferioli1, Erika Rimondi1, Lorenzo Caruso1, Luca M. Neri1 •
University of Ferrara1
01 Feb 2020-Hematological Oncology
TL;DR: This review focuses on modern therapies in ALL that move beyond standard chemotherapy, with a particular emphasis on immunotherapeutic approaches as new treatment strategies.
Abstract: Acute lymphoblastic leukemia (ALL) represents a heterogeneous group of hematologic malignancies, and it is normally characterized by an aberrant proliferation of immature lymphoid cells. Moreover, dysregulation of multiple signaling pathways that normally regulate cellular transcription, growth, translation, and proliferation is frequently encountered in this malignancy. ALL is the most frequent tumor in childhood, and adult ALL patients still correlate with poor survival. This review focuses on modern therapies in ALL that move beyond standard chemotherapy, with a particular emphasis on immunotherapeutic approaches as new treatment strategies. Bi-specific T-cell Engagers (BiTE) antibodies, the chimeric antigen receptor (CAR)-T cells, or CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats [CRISPR]-associated nuclease 9) represent other new innovative approaches for this disease. Target and tailored therapy could make the difference in previously untreatable cases, i.e., precision and personalized medicine. Clinical trials will help to select the most efficient novel therapies in ALL management and to integrate them with existing treatments to achieve durable cures.

8 citations

Cites background from "Activation of Akt is associated wit..."

  • ...SMIs have been or are in the clinics not only for the T-ALL subtype but also for the B-ALL subtype,(47-51) since aberrant activity of the PI3K/ Akt/mTOR pathway correlates with poor prognosis both in adults and in pediatric B-ALL patients.(52,53) PI3K inhibitors comprise pan p110 PI3K inhibitors and isoformselective drugs....

    [...]

Journal Article•DOI•
Targeting Akt/PKB in Pediatric Tumors: A Review From Preclinical to Clinical Trials.

[...]

B Toson, Isadora Serraglio Fortes, Rafael Roesler, S. F. Andrade
01 Aug 2022-Pharmacological research
TL;DR: In this paper , the serine/threonine kinase Akt is a major player in the PI3K/Akt/mTOR signaling pathway, and its modulation impacts multiple cellular processes such as growth, proliferation, and survival.
Abstract: The serine/threonine kinase Akt is a major player in the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway, and its modulation impacts multiple cellular processes such as growth, proliferation, and survival. Several abnormalities in this pathway have been documented over the years, and these alterations were shown to have great implications in tumorigenesis and resistance to chemotherapy. Thus, multiple Akt inhibitors have been developed and tested in adult tumors, and some of them are currently undergoing phase I, II, and III clinical trials for distinct cancers that arise during adulthood. Despite that, the impact of these inhibitors is still not fully understood in pediatric tumors, and Akt-specific targeting seems to be a promising approach to treat children affected by cancers. This review summarizes recent available evidence of Akt inhibitors in pediatric cancers, from both preclinical and clinical studies. In short, we demonstrate the impact that Akt inhibition provides in tumorigenesis, and we suggest targeting the PI3K/Akt/mTOR signaling pathway, alone or in combination with other inhibitors, is a feasible tool to achieve better outcomes in pediatric tumors.

7 citations

References
More filters
Journal Article•DOI•
AKT/PKB signaling: navigating downstream.

[...]

Brendan D. Manning1, Lewis C. Cantley2•
Harvard University1, Beth Israel Deaconess Medical Center2
29 Jun 2007-Cell
TL;DR: Those Akt substrates that are most likely to contribute to the diverse cellular roles of Akt, which include cell survival, growth, proliferation, angiogenesis, metabolism, and migration are discussed.

5,505 citations

"Activation of Akt is associated wit..." refers background in this paper

  • ...Akt binds to phosphatidylinositol-3,4,5-triphosphate on the plasma membrane where Akt is activated by phosphorylation at threonine308 (T308) and serine473 (S473) residues....

    [...]

  • ...Antibodies against Akt and PAkt on S473 and HRP-linked secondary antibody were purchased from Cell Signaling Technology Inc. (Irvine, CA) and antibodies against b-actin and Myc tag from Santa Cruz Biotechnology Inc. and Millipore Corp. (Billerica, MA), respectively....

    [...]

  • ...30-Phosphoinositide-dependent kinase 1 phosphorylates the activation loop of Akt at T308, although the mammalian target of rapamycin complex 2 phosphorylates Akt at the hydrophobic motif S473 [7]....

    [...]

Journal Article•DOI•
The activation of Akt/PKB signaling pathway and cell survival

[...]

Gang Song1, Gaoliang Ouyang1, Shideng Bao2, Shideng Bao1•
Xiamen University1, Duke University2
01 Jan 2005-Journal of Cellular and Molecular Medicine
TL;DR: Akt/PKB plays important roles in the signaling pathways in response to growth factors and other extracellular stimuli to regulate several cellular functions including nutrient metabolism, cell growth, apoptosis and survival.
Abstract: Akt/PKB is a serine/threonine protein kinase that functions as a critical regulator of cell survival and proliferation. Akt/PKB family comprises three highly homologous members known as PKBalpha/Akt1, PKBbeta/Akt2 and PKBgamma/Akt3 in mammalian cells. Similar to many other protein kinases, Akt/PKB contains a conserved domain structure including a specific PH domain, a central kinase domain and a carboxyl-terminal regulatory domain that mediates the interaction between signaling molecules. Akt/PKB plays important roles in the signaling pathways in response to growth factors and other extracellular stimuli to regulate several cellular functions including nutrient metabolism, cell growth, apoptosis and survival. This review surveys recent developments in understanding the molecular mechanisms of Akt/PKB activation and its roles in cell survival in normal and cancer cells.

1,811 citations

"Activation of Akt is associated wit..." refers background in this paper

  • ...We assume that other pathways aside from P-glycoprotein play an important role in MDR in Nalm-6/Akt, such as expression of another ATP-binding cassette transporter, inhibition of BAD, inhibition of Caspase-9, activation of NF-kB, inhibition of p53, and so forth [6,24]....

    [...]

  • ...Activation of the PI3K/Akt pathway induces activation of nuclear factor-kB and Bcl-2 and inhibition of Bcl-2 antagonist of cell death (BAD), Caspase-9 and p53 [6]....

    [...]

  • ...The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is a prototypic survival pathway that plays a central role in diverse cellular functions including insulin metabolism, protein synthesis, proliferation, and apoptosis [5,6]....

    [...]

Journal Article•DOI•
P-glycoprotein: from genomics to mechanism

[...]

Suresh V. Ambudkar, Chava Kimchi-Sarfaty, Zuben E. Sauna, Michael M. Gottesman
20 Oct 2003-Oncogene
TL;DR: A model for how ATP energizes transfer of substrates from these binding sites on P-gp to the outside of the cell is proposed, which accounts for the apparent stoichiometry of two ATPs hydrolysed per molecule of drug transported.
Abstract: Resistance to chemically different natural product anti-cancer drugs (multidrug resistance, or MDR) results from decreased drug accumulation, resulting from expression of one or more ATP-dependent efflux pumps. The first of these to be identified was P-glycoprotein (P-gp), the product of the human MDR1 gene, localized to chromosome 7q21. P-gp is a member of the large ATP-binding cassette (ABC) family of proteins. Although its crystallographic 3-D structure is yet to be determined, sequence analysis and comparison to other ABC family members suggest a structure consisting of two transmembrane (TM) domains, each with six TM segments, and two nucleotide-binding domains. In the epithelial cells of the gastrointestinal tract, liver, and kidney, and capillaries of the brain, testes, and ovaries, P-gp acts as a barrier to the uptake of xenobiotics, and promotes their excretion in the bile and urine. Polymorphisms in the MDR1 gene may affect the pharmacokinetics of many commonly used drugs, including anticancer drugs. Substrate recognition of many different drugs occurs within the TM domains in multiple-overlapping binding sites. We have proposed a model for how ATP energizes transfer of substrates from these binding sites on P-gp to the outside of the cell, which accounts for the apparent stoichiometry of two ATPs hydrolysed per molecule of drug transported. Understanding of the biology, genetics, and biochemistry of P-gp promises to improve the treatment of cancer and explain the pharmacokinetics of many commonly used drugs.

985 citations

"Activation of Akt is associated wit..." refers background in this paper

  • ...P-glycoprotein is a member of ATP-binding cassette transporters that extract antitumor drugs from cytoplasm and which reduce intracellular drug concentrations to sub-lethal levels [20,21]....

    [...]

  • ...The expression of P-glycoprotein, encoded by the MDR1 gene, is often associated with MDR in tumor cells [20,27]....

    [...]

  • ...In patients with leukemias, lymphomas, and multiple myeloma, P-glycoprotein expression, which is very low at presentation, is occasionally enhanced during administration of long-term chemotherapy or when the disease recurs [20]....

    [...]

Journal Article•DOI•
Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy.

[...]

Hans-Guido Wendel1, Elisa de Stanchina1, Jordan S. Fridman2, Jordan S. Fridman1, Abba Malina3, Sagarika Ray1, Scott C. Kogan4, Carlos Cordon-Cardo5, Jerry Pelletier3, Scott W. Lowe1 •
Cold Spring Harbor Laboratory1, Incyte2, McGill University3, University of California, San Francisco4, Memorial Sloan Kettering Cancer Center5
18 Mar 2004-Nature
TL;DR: It is shown that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects.
Abstract: Evading apoptosis is considered to be a hallmark of cancer, because mutations in apoptotic regulators invariably accompany tumorigenesis. Many chemotherapeutic agents induce apoptosis, and so disruption of apoptosis during tumour evolution can promote drug resistance. For example, Akt is an apoptotic regulator that is activated in many cancers and may promote drug resistance in vitro. Nevertheless, how Akt disables apoptosis and its contribution to clinical drug resistance are unclear. Using a murine lymphoma model, we show that Akt promotes tumorigenesis and drug resistance by disrupting apoptosis, and that disruption of Akt signalling using the mTOR inhibitor rapamycin reverses chemoresistance in lymphomas expressing Akt, but not in those with other apoptotic defects. eIF4E, a translational regulator that acts downstream of Akt and mTOR, recapitulates Akt's action in tumorigenesis and drug resistance, but is unable to confer sensitivity to rapamycin and chemotherapy. These results establish Akt signalling through mTOR and eIF4E as an important mechanism of oncogenesis and drug resistance in vivo, and reveal how targeting apoptotic programmes can restore drug sensitivity in a genotype-dependent manner.

949 citations

"Activation of Akt is associated wit..." refers background in this paper

  • ...Furthermore, murine models of Akt activation have shown that constitutively active Akt causes myeloproliferative disease [30], promotes drug resistance, and shortens tumor-free survival [25]....

    [...]

Journal Article•DOI•
The Akt-mTOR tango and its relevance to cancer.

[...]

Nissim Hay1•
University of Illinois at Chicago1
01 Sep 2005-Cancer Cell
TL;DR: Two recent studies used mouse genetics to assess the roles of PTEN and TSC2 in cancer, underscoring the importance of Akt-mTOR interplay for cancer progression and therapy.

767 citations

"Activation of Akt is associated wit..." refers background in this paper

  • ...The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is a prototypic survival pathway that plays a central role in diverse cellular functions including insulin metabolism, protein synthesis, proliferation, and apoptosis [5,6]....

    [...]

  • ...The PI3K/Akt signaling pathway controls the expression and function of many proteins that are necessary for cell survival, growth, and anti-apoptosis [5]....

    [...]

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