MicroRNA-451 Regulates LKB1/AMPK Signaling and Allows Adaptation to Metabolic Stress in Glioma Cells

Godlewski, Jakub; Nowicki, Michal O.; Bronisz, Agnieszka; Nuovo, Gerard J.; Palatini, Jeff; Lay, Michael De; Brocklyn, James Van; Ostrowski, Michael C.; Chiocca, E. Antonio; Lawler, Sean E.

doi:10.1016/j.molcel.2010.02.018

Cited by 388 publications

(452 citation statements)

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“…4 miRNA dysregulation is a common feature of neoplasia and numerous miRNAs have been characterized as oncogenes or tumor suppressors in many cancers including in glioblastoma (GBM). 3,[5][6][7][8][9][10][11] microRNA-134 (miR-134) has been implicated in the regulation of physiological and developmental processes. It was shown to promote mouse embryonic stem-cell differentiation, dendritogenesis, and stage-specific cortical development.…”

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confidence: 99%

Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma

Zhang

Mueller

et al. 2014

Cell Death Differ

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Receptor tyrosine kinases (RTKs) are co-deregulated in a majority of glioblastoma (GBM), the most common and most deadly brain tumor. We show that the RTKs MET, EGFR, and PDGFR regulate microRNA-134 (miR-134) in GBM. We find that miR-134 is downregulated in human tumors and cancer stem cells and that its expression inversely correlates with the activation of MET, EGFR, and PDGFR. We demonstrate that miR-134 inhibits cancer cell and stem-cell proliferation, survival, and xenograft growth, as well as cancer stem-cell self-renewal and stemness. We identify KRAS and STAT5B as targets of miR-134, and establish molecular and functional links between RTKs, miR-134, KRAS/STAT5B and malignancy in vitro and in vivo. We show that miR-134 induction is required for the anti-tumor effects of RTK inhibitors. We also uncover the molecular pathways through which RTKs regulate miR-134 expression and demonstrate the involvement of MAPK signaling and the KLF4 transcription factor. We therefore identify miR-134 as a novel RTK-regulated tumor-suppressive hub that mediates RTK and RTK-inhibitor effects on GBM malignancy by controlling KRAS and STAT5B. Cell Death and Differentiation (2014) 21, 720-734; doi:10.1038/cdd.2013; published online 17 January 2014 microRNAs (miRNAs) regulate a wide variety of physiological and pathological processes. 1-3 miRNAs modulate protein expression by binding to the 3 0 untranslated region (3 0 UTR) of target mRNA and promoting RNA degradation and/or inhibiting translation. Single miRNAs can regulate multiple molecules, highlighting a powerful mechanism for the regulation of redundant and cross-talking signal transduction pathways. 4 miRNA dysregulation is a common feature of neoplasia and numerous miRNAs have been characterized as oncogenes or tumor suppressors in many cancers including in glioblastoma (GBM). 3,[5][6][7][8][9][10][11] microRNA-134 (miR-134) has been implicated in the regulation of physiological and developmental processes. It was shown to promote mouse embryonic stem-cell differentiation, dendritogenesis, and stage-specific cortical development. 12-17 miR-134 is downregulated by SIRT1 and involved in synaptic plasticity and memory formation. 18 miR-134 expression is regulated by MEF2 in dendritogenesis 14 and GBM. 19 GBM is the most common and most deadly primary malignant brain tumor. 20,21 The Cancer Genome Atlas and other studies have shown that aberrant expression or activation of the receptor tyrosine kinases (RTKs) EGFR, MET, and PDGFR occurs in a majority of GBM and correlates with poor prognosis. 22 Importantly, multiple RTKs are co-activated in the same GBM tumors and tumor cells. 23,24 KRAS, STAT3, and STAT5 are activated by RTKs and mediate their oncogenic effects. [25][26][27][28] The failure of current treatments for GBM is arguably due to the presence in the tumors of GBM stem cells (GSCs) that are resistant to radioand chemo-therapy and capable of maintaining and propagating the tumors. 29-31 EGFR, MET, PDGFR, and miRNAs have been implicated in the regulation of GSC f...

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confidence: 99%

Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma

Zhang

Mueller

et al. 2014

Cell Death Differ

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“…Based on these reports, we hypothesized that activation of the LKB1-AMPK signaling pathway mediates the suppressive effect of probucol on glioma cell proliferation. In fact, it has been reported that activation of LKB1-AMPK signaling induces apoptosis in human glioblastoma cells [16][17][18][19] . Here, we provide evidence of a novel molecular mechanism in which probucol activates AMPK to inhibit glioma cell growth through a 26S-proteasome-dependent signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Probucol suppresses human glioma cell proliferation in vitro via ROS production and LKB1-AMPK activation

et al. 2014

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Aim: Probucol, an anti-hyperlipidemic drug, has been reported to exert antitumor activities at various stages of tumor initiation, promotion and progression. In this study we examined whether the drug affected glioma cell growth in vitro and the underlying mechanisms. Methods: Human glioma U87 and glioblastoma SF295 cell lines were used. Cell proliferation was accessed using the cell proliferation assay and BrdU incorporation. The phosphorylation of AMPK, liver kinase B1 (LKB1) and p27 Kip1 was detected by Western blot. The activity of 26S proteasome was assessed with an in situ fluorescent substrate. siRNAs were used to suppress the expression of the relevant signaling proteins. Results: Treatment of U87 glioma cells with probucol (10-100 μmol/L) suppressed the cell proliferation in dose-and time-dependent manners. Meanwhile, probucol markedly increased the ROS production, phosphorylation of AMPK at Thr172 and LKB1 at Ser428 in the cells. Furthermore, probucol significantly decreased 26S proteasome activity and increased p27 Kip1 protein level in the cells in an AMPK-dependent manner. Probucol-induced suppression of U87 cell proliferation could be reversed by pretreatment with tempol (a superoxide dismutase mimetic), MG132 (proteasome inhibitor) or compound C (AMPK inhibitor), or by gene silencing of LKB1, AMPK or p27 Kip1 . Similar results were observed in probucol-treated SF295 cells. Conclusion: Probucol suppresses human glioma cell proliferation in vitro via ROS production and LKB1-AMPK activation, which reduces 26S proteasome-dependent degradation of p27 Kip1 .

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“…Moreover, the levels of both miRNAs were found to be markedly higher in patients in comparison with the levels in healthy control subjects. Another study also found that mature miR-451 was expressed at a higher level in glioblastoma multiforme tissues than in matched adjacent normal brain tissue (20,21). These data indicated that the expression of miR-451 was associated with disease states and was cell-specific, supporting the clinical value of miR-451 as a diagnostic biomarker in human cancers.…”

Section: Mir-451 In Cancer Diagnosismentioning

confidence: 83%

“…Early studies have also highlighted the roles of miR-144/451 in human cancers. Many studies have established that miR-451 is widely dysregulated in human malignancies, including in lung cancer (14,15), gastric cancer (16), breast cancer (17,18), glioma (19)(20)(21), and leukemia (22), indicating that miR-451 might play a critical role in oncogenesis. In this review, we focus on the noncanonical biogenesis pathway for miR-451 and its roles in erythroid differentiation.…”

Section: Introductionmentioning

confidence: 99%

The Potential Role of miR-451 in Cancer Diagnosis, Prognosis, and Therapy

Pan

Wang

2013

Molecular Cancer Therapeutics

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MicroRNAs (miRNA) are small noncoding RNAs that converge to maintain an intrinsic balance of various processes, including cell proliferation, differentiation, and apoptosis. Recent research efforts have been devoted to translating these basic discoveries into applications that could improve the early diagnosis and therapeutic outcome of patients with cancer. Early studies have shown that miRNA-451 (miR-451) is widely dysregulated in human cancers and plays a critical role in tumorigenesis and tumor progression. In this review, we summarize the potential use of miR-451 for cancer diagnosis, prognosis, and treatment. In addition, we discuss the possible mechanisms of miR-451 dysregulation and future challenges in development of miR-451 as a noninvasive biomarker and a potential therapeutic target in human cancers.

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MicroRNA-451 Regulates LKB1/AMPK Signaling and Allows Adaptation to Metabolic Stress in Glioma Cells

Cited by 388 publications

References 53 publications

Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma

Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma

Probucol suppresses human glioma cell proliferation in vitro via ROS production and LKB1-AMPK activation

The Potential Role of miR-451 in Cancer Diagnosis, Prognosis, and Therapy

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