TY - JOUR
T1 - p27Kip1 mediates addiction of ovarian cancer cells to MYCC (c-MYC) and their dependence on MYC paralogs
AU - Prathapam, Tulsiram
AU - Aleshin, Alexey
AU - Guan, Yinghui
AU - Gray, Joe W.
AU - Martin, G. Steven
PY - 2010/10/15
Y1 - 2010/10/15
N2 - The MYCC (c-MYC) gene is amplified in 30-60% of human ovarian cancers. We assessed the functional significance of MYCC amplification by siRNA inhibition of MYCC or MYC paralogs in a panel of ovarian cancer cell lines expressing varying levels of MYCC. Inactivation of MYCC inhibited cell proliferation and induced replicative senescence only in lines with amplified MYCC, indicating that these cells are addicted to continued MYCC overexpression. In contrast, siRNA knockdown of all three MYC isoforms inhibited proliferation of MYCC nonamplified ovarian cancer cells without inducing replicative senescence, and did not inhibit the proliferation of telomerase-immortalized ovarian surface epithelial cells. The arrest induced by MYCC knockdown was accompanied by an increase in the level of the Cdk inhibitor p27Kip1 and a decrease in cyclin A expression and Cdk2 activity, and could be reversed by RNAi knockdown of p27Kip1 or Rb, or by overexpression of cyclin A/Cdk2. The arrest induced by knockdown of all three MYC isoforms could similarly be reversed by p27Kip1 knockdown. Our findings indicate that the addiction of MYCC-amplified ovarian cancer cells to MYCC differs from the dependence of MYCC non-amplified cancer cells on MYC paralogs, but both are mediated, at least in part, by p27Kip1. They also suggest that growth of ovarian cancers may be blocked by inhibition of MYCC or MYC paralogs.
AB - The MYCC (c-MYC) gene is amplified in 30-60% of human ovarian cancers. We assessed the functional significance of MYCC amplification by siRNA inhibition of MYCC or MYC paralogs in a panel of ovarian cancer cell lines expressing varying levels of MYCC. Inactivation of MYCC inhibited cell proliferation and induced replicative senescence only in lines with amplified MYCC, indicating that these cells are addicted to continued MYCC overexpression. In contrast, siRNA knockdown of all three MYC isoforms inhibited proliferation of MYCC nonamplified ovarian cancer cells without inducing replicative senescence, and did not inhibit the proliferation of telomerase-immortalized ovarian surface epithelial cells. The arrest induced by MYCC knockdown was accompanied by an increase in the level of the Cdk inhibitor p27Kip1 and a decrease in cyclin A expression and Cdk2 activity, and could be reversed by RNAi knockdown of p27Kip1 or Rb, or by overexpression of cyclin A/Cdk2. The arrest induced by knockdown of all three MYC isoforms could similarly be reversed by p27Kip1 knockdown. Our findings indicate that the addiction of MYCC-amplified ovarian cancer cells to MYCC differs from the dependence of MYCC non-amplified cancer cells on MYC paralogs, but both are mediated, at least in part, by p27Kip1. They also suggest that growth of ovarian cancers may be blocked by inhibition of MYCC or MYC paralogs.
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U2 - 10.1074/jbc.M110.151902
DO - 10.1074/jbc.M110.151902
M3 - Article
C2 - 20647308
AN - SCOPUS:77957758151
SN - 0021-9258
VL - 285
SP - 32529
EP - 32538
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 42
ER -