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Department of Pathology and the Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania

Requests for reprints: Demetrius M. Kokkinakis, Division of Basic Research, Hillman Cancer Center, University of Pittsburgh Cancer Institute, UPCI Research Pavillion, Room G12.e, 5117 Centre Avenue, Pittsburgh, PA 15213-1863. Phone: 412-623-1110; Fax: 412-623-4747. E-mail: kokkinakisdm{at}upmc.edu

The effect of methionine deprivation (methionine stress) on the proliferation, survival, resistance to chemotherapy, and regulation of gene and protein expression in pancreatic tumor lines is examined. Methionine stress prevents successful mitosis and promotes cell cycle arrest and accumulation of cells with multiple micronuclei with decondensed chromatin. Inhibition of mitosis correlates with CDK1 down-regulation and/or inhibition of its function by Tyr¹⁵ phosphorylation or Thr¹⁶¹ dephosphorylation. Inhibition of cell cycle progression correlates with loss of hyperphosphorylated Rb and up-regulation of p21 via p53 and/or transforming growth factor-ß (TGF-ß) activation depending on p53 status. Although methionine stress–induced toxicity is not solely dependent on p53, the gain in p21 and loss in CDK1 transcription are more enhanced in wild-type p53 tumors. Up-regulation of SMAD7, a TGF-ß signaling inhibitor, suggests that SMAD7 does not restrict the TGF-ß-mediated induction of p21, although it may prevent up-regulation of p27. cDNA oligoarray analysis indicated a pleiotropic response to methionine stress. Cell cycle and mitotic arrest is in agreement with up-regulation of NF2, ETS2, CLU, GADD45, GADD45ß, and GADD45 and down-regulation of AURKB, TOP2A, CCNA, CCNB, PRC1, BUB1, NuSAP, IFI16, and BRCA1. Down-regulation of AREG, AGTR1, M-CSF, and EGF, IGF, and VEGF receptors and up-regulation of GNA11 and IGFBP4 signify loss of growth factor support. PIN1, FEN1, and cABL up-regulation and LMNB1, AREG, RhoB, CCNG, TYMS, F3, and MGMT down-regulation suggest that methionine stress sensitizes the tumor cells to DNA-alkylating drugs, 5-fluorouracil, and radiation. Increased sensitivity of pancreatic tumor cell lines to temozolomide is shown under methionine stress conditions and is attributed in part to diminished O⁶-methylguanine-DNA methyltransferase and possibly to inhibition of the cell cycle progression.

Note: R.D. Neuner is currently at the Department of Molecular and Cellular Biology, University of Massachusetts, Amherst, MA 01003.

¹ Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 5/ 4/05; revised 6/17/05; accepted 7/15/05.