Abstract
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 Tyr(15) phosphorylation or Thr(161) dephosphorylation. Inhibition of cell cycle progression correlates with loss of hyperphosphorylated Rb and up-regulation of p21 via p53 and/or transforming growth factor-beta (TGF-beta) 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-beta signaling inhibitor, suggests that SMAD7 does not restrict the TGF-beta-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, GADD45alpha, GADD45beta, and GADD45gamma 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 O(6)-methylguanine-DNA methyltransferase and possibly to inhibition of the cell cycle progression.
Highlights
Pancreatic adenocarcinoma is the fourth leading cause of death in the United States, with an estimated incident of 30,000 victims annually
The cell cycle of pancreatic tumor cells was diversely affected by methionine stress (Fig. 2)
Cells with a higher DNA content accumulated in cultures of CAPAN1, CAPAN2, and especially CFPAC1, whereas a G1 arrest was shown in cultures of Panc1 and MiaPaCa2
Summary
Pancreatic adenocarcinoma is the fourth leading cause of death in the United States, with an estimated incident of 30,000 victims annually. The coexpression of RB1 and p53 pathwayrelated proteins, such as p21WAF1/CIP1 and BAX, render a significantly higher survival rate in patients with ductal carcinoma of the pancreas [8]. Research in this laboratory [9] has identified that the two prominent factors in the resistance of pancreatic neoplasms to alkylating chemotherapeutic agents are (a) the high level of O6-methylguanineDNA methyltransferase (MGMT) in the tumor and (b) the widespread mutation of p53 that prevents p53-mediated cell cycle arrest in response to DNA damage [10]. Compounds that restore the binding affinity of mutant p53 to DNA, such as
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
