Loss of NDRG2 expression activates PI3K-AKT signalling via PTEN phosphorylation in ATLL and other cancers

Nakahata, Shingo; Ichikawa, Tomonaga; Maneesaay, Phudit; Saito, Yûsuke; Nagai, K.; Tamura, Tomohide; Manachai, Nawin; Yamakawa, Noriko; Hamasaki, Makoto; Kitabayashi, Issay; Arai, Yasuhito; Kanai, Yae; Taki, Tomohiko; Abe, Takaya; Kanazawa, Hiroshi; Shimoda, Kazuya; Ohshima, Koichi; Horii, Akira; Shima, Hiroshi; Taniwaki, Masafumi; Yamaguchi, Ryoji; Morishita, Kazuhiro

doi:10.1038/ncomms4393

Cited by 136 publications

(170 citation statements)

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“…Loss of function of phosphatases, most notably PTEN, which regulate this pathway, has been demonstrated in ATL (6). It has been demonstrated that inhibition of signaling through mTORC1 inhibits growth of ATL cells (22).…”

Section: Discussionmentioning

confidence: 99%

“…Considering that PI3K is upstream of mTOR, and is activated in ATL and HTLV-1-infected T-cell lines (6,22), we considered that inhibition of PI3K in addition to mTOR would be a superior strategy to inhibition of mTOR or PI3K alone. We compared the effects of the dual PI3K/mTOR inhibitor NVP-BEZ235 with those of the PI3K inhibitor NVP-BKM120 and the mTOR inhibitor RAD001.…”

Section: Superior Growth Inhibitory Activity Of Nvp-bez235 Compared Tmentioning

confidence: 99%

“…This pathway integrates various extracellular stimuli to regulate several cellular processes, such as mRNA translation, cell survival and cell cycle progression (5). The inactive phosphorylated form of phosphatase and tensin homologue (PTEN), a negative PI3K regulator, are often expressed on ATL cells and contribute to constitutive PI3K signaling (6). These pathways could be suitable targets for new therapies for ATL.…”

Section: Introductionmentioning

confidence: 99%

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Effects of NVP‑BEZ235, a dual phosphatidylinositolï¿½3-kinase/mammalian target of rapamycin inhibitor, on HTLV-1-infected T-cell lines

2018

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Abstract. Adult T-cell leukemia (ATL) is an aggressive type of malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). In ATL, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway is constitutively active, promoting cell proliferation, survival and chemoresistance. Thus, the PI3K signaling pathway is an attractive therapeutic target for ATL. In the present study, the effects of RAD001 (an mTOR inhibitor), NVP-BKM120 (a pan-PI3K inhibitor) and NVP-BEZ235 (a novel dual PI3K/mTOR inhibitor) on cultured HTLV-1-infected T-cell lines were compared. The results demonstrated that NVP-BEZ235 was more efficacious compared with RAD001 and NVP-BKM120 at inhibiting cell growth. NVP-BEZ235 exhibited cytostatic rather than cytotoxic effects on various HTLV-1-infected T-cell lines, where it induced cell cycle arrest at G 1 phase. NVP-BEZ235 downregulated cyclin D1, cyclin D2, cyclin E, cyclin dependent kinase (CDK)2 and CDK4 expression, and the phosphorylation of retinoblastoma protein. In C.B-17/Icr-severe combined immune deficiency mice implanted with HTLV-1-infected HUT-102 cells, oral NVP-BEZ235 caused marked retardation of tumor growth compared with the control. The present in vitro and in vivo studies highlight the efficacious dual inhibition of PI3K, and mTOR following NVP-BEZ235 treatment. Thus, the results of the current study provide preclinical rationale for phase I clinical studies to examine the effects of NVP-BEZ235 in patients with ATL.

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Section: Discussionmentioning

confidence: 99%

Section: Superior Growth Inhibitory Activity Of Nvp-bez235 Compared Tmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of NVP‑BEZ235, a dual phosphatidylinositolï¿½3-kinase/mammalian target of rapamycin inhibitor, on HTLV-1-infected T-cell lines

2018

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“…15 In addition, binding of PTEN with the plasma membrane is also regulated by the phosphorylation status of PTEN. [16][17][18] This interaction is delineated in more detail in the following sections.…”

Section: Pten and Tumor Suppressionmentioning

confidence: 99%

The functions of tumor suppressor PTEN in innate and adaptive immunity

Chen

Guo

2017

Cell Mol Immunol

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The tumor suppressor phosphatase and tensin homolog (PTEN) is a lipid and protein phosphatase that is able to antagonize the PI3K/AKT pathway and inhibit tumor growth. PTEN also possesses phosphatase-independent functions. Genetic alterations of PTEN may lead to the deregulation of cell proliferation, survival, differentiation, energy metabolism and cellular architecture and mobility. Although the role of PTEN in tumor suppression is extensively documented and well established, the evidence for its roles in immunity did not start to accumulate until recently. In this review, we will focus on the newly discovered functions of PTEN in the regulation of innate and adaptive immunity, including antiviral responses.

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“…Thus far, direct comprehensive analyses of leukemic cells from ATL patients have identified the intrinsic molecular hallmarks of ATL, which comprise changes in gene expression, producing cytokines, genomic abnormalities, sustained signaling, microRNA (miRNA) deregulation, and epigenetic alterations. [7][8][9][10][11][12][13] Because these organized principles serve the characteristics of ATL itself and are directly associated with its clinical traits, targeting them with mechanismguided combination therapies may yield more effective and durable treatments for aggressive ATL with fewer adverse effects. There is also an urgent need to prevent the onset of the disease in HTLV-1-endemic areas in ways that selectively eliminate HTLV-1-infected cells.…”

Section: Introductionmentioning

confidence: 99%