AKT and PAX3-FKHR cooperation enforces myogenic differentiation blockade in alveolar rhabdomyosarcoma cell

Jothi, Mathivanan; Nishijo, Kochi; Keller, Charles; Mal, Asoke K.

doi:10.4161/cc.11.5.19346

Cited by 24 publications

(30 citation statements)

References 62 publications

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“…Consistent with this, the administration of 2-deoxyglucose (2-DG), a glycolytic inhibitor commonly utilized as a cancer therapeutic, 56 has been reported to sensitize different fusion-positive RMS lines to cell death, 57 suggesting that the Pax3-Foxo1-dependent increased glucose consumption could be rate-limiting for tumor growth. Pax3-Foxo1 also has the ability to elicit downregulation of phosphate and tensin homolog deleted on chromosome 10 (PTEN) gene, 58 a phosphatase which functionally antagonizes PI3K and downstream protein kinases such as AKT, 59,60 therefore increasing the activity of PI3K/AKT/mammalian target of rapamycin (mTOR) pathway 61 (Fig. 3).…”

Section: Pax3-foxo1 Oncoproteinmentioning

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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Section: Pax3-foxo1 Oncoproteinmentioning

confidence: 99%

Uncovering metabolism in rhabdomyosarcoma

Monti

Fanzani

2016

Cell Cycle

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“…PAX genes in subgroups I (PAX1 and PAX9) are less often involved in cancer or their expression is indicative of a more favorable outcome [5]. PAX/Pax (human/mouse) proteins, therefore, serve as tumor markers in several cancers such as rhabdomyosarcoma, melanoma, neuroblastoma, and Ewing's sarcoma [2,6,76]. While PAX expression is very rare in adult tissues, findings support that its expression may be involved in maintaining pluripotency and survival of stem cell populations.…”

Section: Pax3 Plays An Oncogenic Role In Various Types Of Tumorsmentioning

confidence: 99%

PAX3: A Molecule with Oncogenic or Tumor Suppressor Function Is Involved in Cancer

Arasu

Murugan

Essa

et al. 2018

BioMed Research International

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Metastasis is the most deadly aspect of cancer and results from acquired gene regulation abnormalities in tumor cells. Transcriptional regulation is an essential component of controlling of gene function and its failure could contribute to tumor progression and metastasis. During cancer progression, deregulation of oncogenic or tumor suppressive transcription factors, as well as master cell fate regulators, collectively influences multiple steps of the metastasis cascade, including local invasion and dissemination of the tumor to distant organs. Transcription factor PAX3/Pax3, which contributes to diverse cell lineages during embryonic development, plays a major role in tumorigenesis. Mutations in this gene can cause neurodevelopmental disease and the existing literature supports that there is a potential link between aberrant expression of PAX3 genes in adult tissues and a wide variety of cancers. PAX3 function is tissue-specific and could contribute to tumorigenesis either directly as oncogene or as a tumor suppressor by losing its function. In this review, we discuss comprehensively the differential role played by PAX3 in various tissues and how its aberrant expression is implicated in disease development. This review particularly highlights the oncogenic and tumor suppressor role played by PAX3 in different cancers and underlines the importance of precisely identifying tissue-specific role of PAX3 in order to determine its exact role in development of cancer.

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“…Mouse ARMS cell lines U20497T and U20325 were previously described (22, 23). Human ARMS cell lines Rh7, Rh28, Rh30 and Rh41 were provided by Dr. Peter.…”

Section: Methodsmentioning

confidence: 99%

“…C2C12, RD, 293A and Phoenix-Ampho cell lines were authenticated as described previously (23, 24). U20497T-PRSLuc and U20325-PRSLuc cells expressing the PAX3-FOXO1-responsive reporter luciferase (6XPRS-Luc) generated through lentivirus transduction were described previously (23). A similar strategy was applied to generate Rh30-PRSLuc and RD-PRSLuc reporter cells and CMV-driven luciferase reporter U20325-CMVLuc cells.…”

Section: Methodsmentioning

confidence: 99%

Small Molecule Inhibition of PAX3-FOXO1 through AKT Activation Suppresses Malignant Phenotypes of Alveolar Rhabdomyosarcoma

Jothi

Mal

Keller

et al. 2013

Molecular Cancer Therapeutics

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Alveolar rhabdomyosarcoma (ARMS) comprises a rare highly malignant tumor presumed to be associated with skeletal muscle lineage in children. The hallmark of the majority of ARMS is a chromosomal translocation that generates the PAX3-FOXO1 fusion protein, which is an oncogenic transcription factor responsible for the development of the malignant phenotype of this tumor. ARMS cells are dependent to the oncogenic activity of PAX3-FOXO1 and its expression status in ARMS tumors correlates with worst patient outcome, suggesting that blocking this activity of PAX3-FOXO1 may be an attractive therapeutic strategy against this fusion-positive disease. In this study, we screened small-molecule chemical libraries for inhibitors of PAX3-FOXO1 transcriptional activity using a cell-based readout system. We identified the Sarco/Endoplasmic Reticulum Ca2+-ATPases (SERCA) inhibitor thapsigargin as an effective inhibitor of PAX3-FOXO1. Subsequent experiments in ARMS cells demonstrated that activation of AKT by thapsigargin inhibited PAX3-FOXO1 activity via phosphorylation. Moreover, this AKT activation appears to be associated with the effects of thapsigargin on intracellular calcium levels. Furthermore, thapsigargin inhibited the binding of PAX3-FOXO1 to target genes and subsequently promoted its proteosomal degradation. In addition, thapsigargin treatment decreases the growth and invasive capacity of ARMS cells while inducing apoptosis in vitro. Finally, thapsigargin can suppress the growth of an ARMS xenograft tumor in vivo. These data reveal that thapsigargin-induced activation of AKT is an effective mechanism to inhibit PAX3-FOXO1 and a potential agent for targeted therapy against ARMS.

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AKT and PAX3-FKHR cooperation enforces myogenic differentiation blockade in alveolar rhabdomyosarcoma cell

Cited by 24 publications

References 62 publications

Uncovering metabolism in rhabdomyosarcoma

Uncovering metabolism in rhabdomyosarcoma

PAX3: A Molecule with Oncogenic or Tumor Suppressor Function Is Involved in Cancer

Small Molecule Inhibition of PAX3-FOXO1 through AKT Activation Suppresses Malignant Phenotypes of Alveolar Rhabdomyosarcoma

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