Synthetic lethal interaction between PI3K/Akt/mTOR and Ras/MEK/ERK pathway inhibition in rhabdomyosarcoma

Guenther, Monika Katharina; Graab, Ulrike; Fulda, Simone

doi:10.1016/j.canlet.2013.05.010

Cited by 60 publications

(66 citation statements)

References 47 publications

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“…Strikingly, a kinomewide siRNA as well as a small-molecule library screen identified PLK1 as top hit. KEGG pathway analysis (string-db.org) showed that several additional candidates are associated with MAPK or phosphatidylinositol signaling, both of which have been previously reported in RMS (29,30).…”

Section: Discussionmentioning

confidence: 75%

“…Therefore, cancer cell-specific functions in G 1 -S transition and DNA replication are suggested beyond its role in regulation of mitosis. Interestingly, PLK1 is associated with the PI3K and MAPK pathways, both of which are thought to play important roles in aRMS (29,30). Hence, PLK1 overexpression might not just be a consequence of enhanced proliferation, but it is likely that PLK1 actively contributes to early carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

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PLK1 Phosphorylates PAX3-FOXO1, the Inhibition of Which Triggers Regression of Alveolar Rhabdomyosarcoma

et al. 2015

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

PLK1 Phosphorylates PAX3-FOXO1, the Inhibition of Which Triggers Regression of Alveolar Rhabdomyosarcoma

et al. 2015

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“…78 Finallly, the cardiac-specific deletion of the von Hippel-Lindau protein (VHL), an E3 ubiquitin ligase responsible of suppression of HIF levels during normoxia, has been described to favor the formation of highly metastatic cardiac RMS in a mouse model. 79 Taken together, different lines of evidence indicate that the PI3K/AKT and ERK1/2 pathways, often concurrently with the HIF pathway, play a central role for RMS progression; their targeted inhibition was indeed shown to enhance cell death in RMS lines under both normoxic 80 and hypoxic conditions. 81,82 Loss of p53 activity Different regulators in healthy tissues control the glucose metabolism, including p53, AKT, Myc and HIF proteins.…”

Section: Deliberate Activation Of Rtk Pathwaysmentioning

confidence: 99%

Uncovering metabolism in rhabdomyosarcoma

Monti

Fanzani

2016

Cell Cycle

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Rhabdomyosarcoma (RMS) is a myogenic tumor classified as the most frequent soft tissue sarcoma affecting children and adolescents. The histopathological classification includes five different histotypes, with two most predominant referred as to embryonal and alveolar, the latter being characterized by adverse outcome. The current molecular classification identifies two major subsets, those harboring the fused Pax3-Foxo1 transcription factor generating from a recurrent specific translocation (fusion-positive RMS), and those lacking this signature but harboring mutations in the RAS/PI3K/AKT signalling axis (fusion-negative RMS). Since little attention has been devoted to RMS metabolism until now, in this review we summarize the “state of art” of metabolism and discuss how some of the molecular signatures found in this cancer, as observed in other more common tumors, can predict important metabolic challenges underlying continuous cell growth, oxidative stress resistance and metastasis, which could be the subject of future targeted therapies

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“…The eRMS variant is the most treatable and most common subtype representing ~80% of RMS, while aRMS is more aggressive and characterized by a poorer prognosis. The genetic alterations characterizing eRMS commonly involve the loss of heterozygosis on chromosome region 11p15.5 (4), gain of chromosomes (5,6) and mutations on genes involved with growth factor signaling pathways (7)(8)(9)(10)(11)(12)(13)(14)(15). This leads to uncontrolled cell growth and the interruption of proper myogenic differentiation.…”

Section: Introductionmentioning

confidence: 99%

Melatonin decreases cell proliferation, impairs myogenic differentiation and triggers apoptotic cell death in rhabdomyosarcoma cell lines

et al. 2015

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Abstract. Melatonin is a small indole produced by the pineal gland and other tissues, and has numerous functions that aid in the maintenance of the whole body homeostasis, ranging from the regulation of circadian rhythms and sleep to protection from oxidative stress. Melatonin has also been reported to counteract cell growth and chemoresistance in different types of cancer. In the present study, we investigated the effects of exogenous melatonin administration on different human cell lines and primary mouse tumor cultures of rhabdomyosarcoma (RMS), the most frequent soft tissue sarcoma affecting childhood. The results showed that melatonin significantly affected the behavior of RMS cells, leading to inhibition of cell proliferation and impairment of myogenic differentiation followed by increased apoptotic cell death, as observed by immunoblotting analysis of apoptosis-related markers including Bax, Bcl-2 and caspase-3. Similar findings were observed using a combination of microscopy techniques, including scanning/transmission electron and confocal microscopy. Furthermore, melatonin in combination with doxorubicin or cisplatin, two compounds commonly used for the treatment of solid tumors, increased the sensitivity of RMS cells to apoptosis. These data indicated that melatonin may be effective in counteracting RMS tumor growth and chemoresistance. IntroductionSoft tissue sarcomas are tumors arising from mesenchymal cell precursors that are committed towards the morpho genesis of soft tissues such as fat, muscle and deep skin tissues. Rhabdomyosarcoma (RMS) is considered a myogenic tumor and is classified as the most frequent sarcoma affecting children and adolescents (1). The current classification defines five different histotypes, with embryonal (eRMS) and alveolar (aRMS) subsets being the most frequently observed in children <5 years and in adolescents, respectively (2,3). The eRMS variant is the most treatable and most common subtype representing ~80% of RMS, while aRMS is more aggressive and characterized by a poorer prognosis. The genetic alterations characterizing eRMS commonly involve the loss of heterozygosis on chromosome region 11p15.5 (4), gain of chromosomes (5,6) and mutations on genes involved with growth factor signaling pathways (7)(8)(9)(10)(11)(12)(13)(14)(15). This leads to uncontrolled cell growth and the interruption of proper myogenic differentiation. Conversely, the aRMS subset is commonly characterized by the expression of Pax3-forkhead box O1 (FOXO1), a fused transcription factor derived from the chromosomal translocation t(2;13)(q35;q14), which juxtaposes the DNA-binding domain of Pax3 to the potent transactivation domain of FOXO1 (16). In the absence of the original Pax3 transactivation domain, the chimeric protein drives in a constitutive manner the transcription of numerous genes involved in muscle embryogenesis, such as c-MET and FGFR4, essentially maintaining the muscle precursors in a long-lasting proliferative state and thereby facilitating tumor initiation, aggressiveness and me...

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Synthetic lethal interaction between PI3K/Akt/mTOR and Ras/MEK/ERK pathway inhibition in rhabdomyosarcoma

Cited by 60 publications

References 47 publications

PLK1 Phosphorylates PAX3-FOXO1, the Inhibition of Which Triggers Regression of Alveolar Rhabdomyosarcoma

PLK1 Phosphorylates PAX3-FOXO1, the Inhibition of Which Triggers Regression of Alveolar Rhabdomyosarcoma

Uncovering metabolism in rhabdomyosarcoma

Melatonin decreases cell proliferation, impairs myogenic differentiation and triggers apoptotic cell death in rhabdomyosarcoma cell lines

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