Elevated cyclin A associated kinase activity promotes sensitivity of metastatic human cancer cells to DNA antimetabolite drug

  • Authors:
    • Jin Wang
    • Hailin Yin
    • Ashwini Panandikar
    • Varsha Gandhi
    • Subrata Sen
  • View Affiliations

  • Published online on: June 8, 2015     https://doi.org/10.3892/ijo.2015.3037
  • Pages: 782-790
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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.
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August-2015
Volume 47 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Wang J, Yin H, Panandikar A, Gandhi V and Sen S: Elevated cyclin A associated kinase activity promotes sensitivity of metastatic human cancer cells to DNA antimetabolite drug. Int J Oncol 47: 782-790, 2015
APA
Wang, J., Yin, H., Panandikar, A., Gandhi, V., & Sen, S. (2015). Elevated cyclin A associated kinase activity promotes sensitivity of metastatic human cancer cells to DNA antimetabolite drug. International Journal of Oncology, 47, 782-790. https://doi.org/10.3892/ijo.2015.3037
MLA
Wang, J., Yin, H., Panandikar, A., Gandhi, V., Sen, S."Elevated cyclin A associated kinase activity promotes sensitivity of metastatic human cancer cells to DNA antimetabolite drug". International Journal of Oncology 47.2 (2015): 782-790.
Chicago
Wang, J., Yin, H., Panandikar, A., Gandhi, V., Sen, S."Elevated cyclin A associated kinase activity promotes sensitivity of metastatic human cancer cells to DNA antimetabolite drug". International Journal of Oncology 47, no. 2 (2015): 782-790. https://doi.org/10.3892/ijo.2015.3037