title: Elevated cyclin A associated kinase activity promotes sensitivity of metastatic human cancer cells to DNA antimetabolite drug.
abstract: Drug resistance is a major obstacle in successful systemic therapy of metastatic cancer. We analyzed the involvement of cell cycle regulatory proteins in eliciting response to N (phosphonoacetyl)-L-aspartate (PALA), an inhibitor of de novo pyrimidine synthesis, in two metastatic variants of human cancer cell line MDA-MB-435 isolated from lung (L-2) and brain (Br-1) in nude mouse, respectively. L-2 and Br-l cells markedly differed in their sensitivity to PALA. While both cell types displayed an initial S phase delay/arrest, Br-l cells proliferated but most L-2 cells underwent apoptosis. There was distinct elevation in cyclin A, and phosphorylated Rb proteins concomitant with decreased expression of bcl-2 protein in the PALA treated L-2 cells undergoing apoptosis. Markedly elevated cyclin A associated and cdk2 kinase activities together with increased E2F1-DNA binding were detected in these L-2 cells. Induced ectopic cyclin A expression sensitized Br-l cells to PALA by activating an apoptotic pathway. Our findings demonstrate that elevated expression of cyclin A and associated kinase can activate an apoptotic pathway in cells exposed to DNA antimetabolites. Abrogation of this pathway can lead to resistance against these drugs in metastatic variants of human carcinoma cells.
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hailin
authors.initials: H
authors.lastname: Yin
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Panandikar
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Subrata
authors.initials: S
authors.lastname: Sen
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D001932:Brain Neoplasms / Q000378:metabolism / Q000556:secondary*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019925:Cyclin A / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D000964:Antimetabolites, Antineoplastic; D019925:Cyclin A; D001224:Aspartic Acid; C013195:sparfosic acid; D051357:Cyclin-Dependent Kinase 2; D010746:Phosphonoacetic Acid