|
|
Crizotinib-induced antitumour activity in human alveolar rhabdomyosarcoma cells is not solely dependent on ALK and MET inhibition
|
|
|
|
|
نویسنده
|
megiorni f. ,mcdowell h.p. ,camero s. ,mannarino o. ,ceccarelli s. ,paiano m. ,losty p.d. ,pizer b. ,shukla r. ,pizzuti a. ,clerico a. ,dominici c.
|
منبع
|
journal of experimental and clinical cancer research - 2015 - دوره : 34 - شماره : 1
|
چکیده
|
Background: rhabdomyosarcoma (rms) is the most commonly diagnosed malignant soft tissue tumour in children and adolescents. aberrant expression of anaplastic lymphoma kinase (alk) and met gene has been implicated in the malignant progression of rms,especially in the alveolar subtype. this observation suggests that crizotinib (pf-02341066),a kinase inhibitor against alk and met,may have a therapeutic role in rms,although its antitumour activity in this malignancy has not yet been studied. methods: rh4 and rh30 alveolar rms (arms) cell lines were treated with crizotinib and then assessed by using proliferation,viability,migration and colony formation assays. multiple approaches,including flow cytometry,immunofluorescence,western blotting and sirna-based knock-down,were used in order to investigate possible molecular mechanisms linked to crizotinib activity. results: in vitro treatment with crizotinib inhibited alk and met proteins,as well as insulin-like growth factor 1 receptor (igf1r),with a concomitant robust dephosphorylation of akt and erk,two downstream kinases involved in rms cell proliferation and survival. exposure to crizotinib impaired cell growth,and accumulation at g2/m phase was attributed to an altered expression and activation of checkpoint regulators,such as cyclin b1 and cdc2. crizotinib was able to induce apoptosis and autophagy in a dose-dependent manner,as shown by caspase-3 activation/parp proteolytic cleavage down-regulation and by lc3 activation/p62 down-regulation,respectively. the accumulation of reactive oxygen species (ros) seemed to contribute to crizotinib effects in rh4 and rh30 cells. moreover,crizotinib-treated rh4 and rh30 cells exhibited a decreased migratory/invasive capacity and clonogenic potential. conclusions: these results provide a further insight into the molecular mechanisms affected by crizotinib in arms cells inferring that it could be a useful therapeutic tool in arms cancer treatment. © 2015 megiorni et al.
|
کلیدواژه
|
ALK; Alveolar rhabdomyosarcoma; Crizotinib; G2/M arrest; IGF1R; MET
|
آدرس
|
department of paediatrics and infantile neuropsychiatry,sapienza university,viale regina elena 324,rome,00161, Italy, department of paediatrics and infantile neuropsychiatry,sapienza university,viale regina elena 324,rome,00161,italy,department of oncology,alder hey children's nhs foundation trust,eaton road,liverpool,l12 2ap, United Kingdom, department of paediatrics and infantile neuropsychiatry,sapienza university,viale regina elena 324,rome,00161, Italy, department of paediatrics and infantile neuropsychiatry,sapienza university,viale regina elena 324,rome,00161, Italy, department of experimental medicine,sapienza university of rome,viale regina elena 324,rome,00161, Italy, department of paediatrics and infantile neuropsychiatry,sapienza university,viale regina elena 324,rome,00161, Italy, department of paediatric surgery,alder hey children's nhs foundation trust,academic paediatric surgery unit,university of liverpool,eaton road,liverpool,l12 2ap, United Kingdom, department of oncology,alder hey children's nhs foundation trust,eaton road,liverpool,l12 2ap, United Kingdom, department of perinatal and paediatric pathology,alder hey children's nhs foundation trust,eaton road,liverpool,l12 2ap, United Kingdom, department of experimental medicine,sapienza university of rome,viale regina elena 324,rome,00161, Italy, department of paediatrics and infantile neuropsychiatry,sapienza university,viale regina elena 324,rome,00161, Italy, department of paediatrics and infantile neuropsychiatry,sapienza university,viale regina elena 324,rome,00161, Italy
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Authors
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|