Phospho-p70S6K and cdc2/cdk1 as therapeutic targets for diffuse large B-cell lymphoma.
p70S6K/p85S6K and cdc2/cdk1 are members of the serine/threonine protein kinase family. p70S6K/p85S6K is one of the downstream effectors of the PI3K/Akt/mTOR signal transduction pathway. It phosphorylates S6 protein of 40S ribosomal subunit and thus functions in protein synthesis and cell growth. cdc2/cdk1 is a cyclin-dependent protein kinase that controls the cell cycle entry from G2 to M phase. Overexpression of phospho-p70S6K and cdc2/cdk1 has recently been identified in the majority of diffuse large B-cell lymphoma (DLBCL) specimens. Combination of small molecules that target phosphorylation of p70S6K and cdc2/cdk1 synergistically induced cell apoptosis and cell cycle G1 and G2 arrest, suggesting that they are potential molecular targets for DLBCL therapy. This review will summarize recent advances in the study of phospho-p70S6K and cdc2/cdk1 as molecular markers and therapeutic targets for DLBCL. We propose that multilevel inhibition of the PI3K/Akt/mTOR pathway and double brake at the G1 and G2 phases of the cell cycle progression are effective strategies in treating DLBCL that overexpress phospho-p70S6K and cdc2/cdk1.
Zhao
Xianfeng Frank
XF
University of Maryland, Marlene and Stewart Greenebaum Cancer Center, Baltimore, Maryland 21201, USA. xzhao@umm.edu
Gartenhaus
Ronald B
RB
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D018844:Cyclin-Dependent Kinases; D016503:Drug Delivery Systems; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000503:physiopathology; D010766:Phosphorylation / Q000187:drug effects; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism
D019926:Cyclin B; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases