RNA interference-mediated c-MYC inhibition prevents cell growth and decreases sensitivity to radio- and chemotherapy in childhood medulloblastoma cells.
BACKGROUND
With current treatment strategies, nearly half of all medulloblastoma (MB) patients die from progressive tumors. Accordingly, the identification of novel therapeutic strategies remains a major goal. Deregulation of c-MYC is evident in numerous human cancers. In MB, over-expression of c-MYC has been shown to cause anaplasia and correlate with unfavorable prognosis.


METHODS
To study the role of c-MYC in MB biology, we down-regulated c-MYC expression by using small interfering RNA (siRNA) and investigated changes in cellular proliferation, cell cycle analysis, apoptosis, telomere maintenance, and response to ionizing radiation (IR) and chemotherapeutics in a representative panel of human MB cell lines expressing different levels of c-MYC (DAOY wild-type, DAOY transfected with the empty vector, DAOY transfected with c-MYC, D341, and D425).


RESULTS
siRNA-mediated c-MYC down-regulation resulted in an inhibition of cellular proliferation and clonogenic growth, inhibition of G1-S phase cell cycle progression, and a decrease in human telomerase reverse transcriptase (hTERT) expression and telomerase activity. On the other hand, down-regulation of c-MYC reduced apoptosis and decreased the sensitivity of human MB cells to IR, cisplatin, and etoposide. This effect was more pronounced in DAOY cells expressing high levels of c-MYC when compared with DAOY wild-type or DAOY cells transfected with the empty vector.


CONCLUSIONS
In human MB cells, in addition to its roles in growth and proliferation, c-MYC is also a potent inducer of apoptosis. Therefore, targeting c-MYC might be of therapeutic benefit when used sequentially with chemo- and radiotherapy rather than concomitantly.
von Bueren
André O
AO
Neuro-Oncology Program, University Children's Hospital, Zurich, Switzerland. Andre.vonBueren@kispi.uzh.ch
Shalaby
Tarek
T
Oehler-Jänne
Christoph
C
Arnold
Lucia
L
Stearns
Duncan
D
Eberhart
Charles G
CG
Arcaro
Alexandre
A
Pruschy
Martin
M
Grotzer
Michael A
MA
D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003131:Combined Modality Therapy; D015536:Down-Regulation / Q000187:drug effects / Q000528:radiation effects; D004358:Drug Therapy; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D011839:Radiation, Ionizing; D011878:Radiotherapy; D019098:Telomerase / Q000235:genetics / Q000378:metabolism
D016271:Proto-Oncogene Proteins c-myc; D019098:Telomerase