Lovastatin inhibits proliferation of pancreatic cancer cell lines with mutant as well as with wild-type K-ras oncogene but has different effects on protein phosphorylation and induction of apoptosis.

  • Authors:
    • C Müller
    • A G Bockhorn
    • S Klusmeier
    • M Kiehl
    • C Roeder
    • H Kalthoff
    • O M Koch
  • View Affiliations

  • Published online on: March 1, 1998     https://doi.org/10.3892/ijo.12.3.717
  • Pages: 717-740
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Abstract

Besides its pharmacological effect on cholesterol biosynthesis, lovastatin inhibits p21ras proteins by substrate depletion for post-translational protein farnesylation and geranylation. This inhibition has previously been used to reverse cell proliferation after cellular transformation by the mutant p21ras oncogene. We investigated the biological effects of lovastatin on two pancreatic carcinoma cell lines. The SW-850 cell line contained the k-ras wild-type gene and the A818-4 cell line contained the mutant gene with a point mutation at codon 12 (GGTZCGT; glyZarg). Lovastatin inhibited the proliferation of pancreatic carcinoma cells dose-dependently showing an IC20-30 at 5 microM and IC40-50 at 10 microM. Proliferation of both cancer cell lines, A818-4 (p21ras-M) and SW-850 (p21ras-WT) were inhibited to a very similar extent. After 24 h of drug exposure, cell cycle arrest in G1 and G2/M-phase occurred in a large proportion of cells. At this time, neither cell line showed alteration of protein phosphorylation and did not undergo apoptosis. However, after 72 h of drug exposure, lovastatin significantly decreased protein phosphorylation on tyrosine, serine and threonine residues in A818-4 (p21ras-M) cells. Only a minute reduction of protein phosphorylation was detected in SW-850 (p21ras-WT) cells. Apoptosis occurred in both cell lines, but the SW-850 (p21ras-WT) showed a higher percentage of apoptotic cells than the A818-4 (p21ras-M). In conclusion, there is further evidence for a growth inhibitory effect on cancer cells regardless of the ras mutation status. However, as the effects on protein phosphorylation and induction of apoptosis differed between the mutant and wild-type cell lines, the mechanism of action of lovastatin may depend on partially different mechanisms.

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Mar 1998
Volume 12 Issue 3

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

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Spandidos Publications style
Müller C, Bockhorn A, Klusmeier S, Kiehl M, Roeder C, Kalthoff H and Koch O: Lovastatin inhibits proliferation of pancreatic cancer cell lines with mutant as well as with wild-type K-ras oncogene but has different effects on protein phosphorylation and induction of apoptosis.. Int J Oncol 12: 717-740, 1998
APA
Müller, C., Bockhorn, A., Klusmeier, S., Kiehl, M., Roeder, C., Kalthoff, H., & Koch, O. (1998). Lovastatin inhibits proliferation of pancreatic cancer cell lines with mutant as well as with wild-type K-ras oncogene but has different effects on protein phosphorylation and induction of apoptosis.. International Journal of Oncology, 12, 717-740. https://doi.org/10.3892/ijo.12.3.717
MLA
Müller, C., Bockhorn, A., Klusmeier, S., Kiehl, M., Roeder, C., Kalthoff, H., Koch, O."Lovastatin inhibits proliferation of pancreatic cancer cell lines with mutant as well as with wild-type K-ras oncogene but has different effects on protein phosphorylation and induction of apoptosis.". International Journal of Oncology 12.3 (1998): 717-740.
Chicago
Müller, C., Bockhorn, A., Klusmeier, S., Kiehl, M., Roeder, C., Kalthoff, H., Koch, O."Lovastatin inhibits proliferation of pancreatic cancer cell lines with mutant as well as with wild-type K-ras oncogene but has different effects on protein phosphorylation and induction of apoptosis.". International Journal of Oncology 12, no. 3 (1998): 717-740. https://doi.org/10.3892/ijo.12.3.717