Role of GAS5 noncoding RNA in mediating the effects of rapamycin and its analogues on mantle cell lymphoma cells.
BACKGROUND
Inhibition of the mammalian target of rapamycin (mTOR) pathway is a promising strategy for the treatment of mantle cell lymphoma (MCL). ncRNA growth arrest-specific 5 (GAS5), a 5' terminal oligopyrimidine (5'TOP) RNA regulated by the mTOR pathway, is necessary and sufficient for normal growth arrest in leukemic and untransformed human lymphocytes.


METHODS
We downregulated endogenous GAS5 in mantle cell lymphoma cell lines using RNA interference before treatment with several rapalogues. The effect of GAS5 downregulation was monitored by 3 independent analyses of cell viability, DNA synthesis, and colony-forming ability.


RESULTS
Downregulation of GAS5 substantially reduced the effects of each rapalogue on cell viability, DNA synthesis, and colony-forming ability.


CONCLUSIONS
Stimulation of expression of candidate tumor suppressor GAS5 is responsible for much of the cytotoxic and cytostatic effects of rapalogues in MCL, suggesting that improved targeting of this pathway may allow improvements in the therapy of this intractable lymphoma.
Institute for Science and Technology in Medicine, Huxley Building, Keele University, Keele, United Kingdom.
Mirna
M
Mourtada-Maarabouni
Institute for Science and Technology in Medicine, Huxley Building, Keele University, Keele, United Kingdom. Electronic address: g.t.williams@keele.ac.uk.
Gwyn T
GT
Williams
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
D000903:Antibiotics, Antineoplastic; C561567:GAS5 long non-coding RNA, human; D047428:Protein Kinase Inhibitors; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
Chemotherapy; Non-Hodgkin lymphoma; Rapamycin; mTOR; ncRNA