Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27Kip1 phosphorylation on Thr187 and accumulates p27Kip1 in the nucleus: implications for breast cancer therapy.
We describe the design of a potent and selective peptidomimetic inhibitor of geranylgeranyltransferase I (GGTI), GGTI-2418, and its methyl ester GGTI-2417, which increases the levels of the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1) and induces breast tumor regression in vivo. Experiments with p27(Kip1) small interfering RNA in breast cancer cells and p27(Kip1) null murine embryonic fibroblasts demonstrate that the ability of GGTI-2417 to induce cell death requires p27(Kip1). GGTI-2417 inhibits the Cdk2-mediated phosphorylation of p27(Kip1) at Thr187 and accumulates p27(Kip1) in the nucleus. In nude mouse xenografts, GGTI-2418 suppresses the growth of human breast tumors. Furthermore, in ErbB2 transgenic mice, GGTI-2418 increases p27(Kip1) and induces significant regression of breast tumors. We conclude that GGTIs' antitumor activity is, at least in part, due to inhibiting Cdk2-dependent p27(Kip1) phosphorylation at Thr187 and accumulating nuclear p27(Kip1). Thus, GGTI treatment might improve the poor prognosis of breast cancer patients with low nuclear p27(Kip1) levels.
Kazi
Aslamuzzaman
A
Drug Discovery Program, Moffitt Cancer Center, Tampa, FL 33612, USA.
Carie
Adam
A
Blaskovich
Michelle A
MA
Bucher
Cynthia
C
Thai
Van
V
Moulder
Stacy
S
Peng
Hairuo
H
Carrico
Dora
D
Pusateri
Erin
E
Pledger
Warren J
WJ
Berndt
Norbert
N
Hamilton
Andrew
A
Sebti
Saïd M
SM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000187:drug effects; D017368:Protein Prenylation / Q000187:drug effects*; D013912:Threonine / Q000378:metabolism
D000970:Antineoplastic Agents; D050760:Cyclin-Dependent Kinase Inhibitor p27; D013912:Threonine; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2