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Carcinogenic aspects of protein phosphatase 1 and 2A inhibitors

Hirota Fujiki1, Masami Suganuma

  • 1Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan. hfujiki@ph.bunri-u.ac.jp

Progress in Molecular and Subcellular Biology
|February 3, 2009
PubMed

Insights

Okadaic acid and other marine toxins promote tumors by inhibiting protein phosphatases 1 and 2A (PP1 and PP2A). This sustained protein phosphorylation mechanism is a general pathway for tumor promotion across various organs.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Toxicology

Background:

  • Okadaic acid is a potent tumor promoter that functions by inhibiting protein phosphatases 1 and 2A (PP1 and PP2A).
  • This mechanism of tumor promotion differs from that of classic promoters like phorbol ester.
  • Other PP1 and PP2A inhibitors, such as dinophysistoxin-1, calyculins, microcystin-LR, and nodularin, are derived from marine organisms.

Purpose of the Study:

  • To review the structural features, tumor-promoting activities, and biochemical/biological effects of marine-derived PP1 and PP2A inhibitors.
  • To investigate the general applicability of PP1 and PP2A inhibition as a tumor promotion mechanism across different organs.
  • To support the concept of endogenous tumor promoters in human cancer development.

Main Methods:

  • Review of existing literature on marine-derived PP1 and PP2A inhibitors.
  • Analysis of structural features, including the crystal structure of PP1-inhibitor complexes.
  • Evaluation of tumor-promoting activities in animal models (mouse skin, rat glandular stomach, rat liver) initiated with various carcinogens.

Main Results:

  • Marine-derived compounds like dinophysistoxin-1, calyculins, microcystin-LR, and nodularin are potent inhibitors of PP1 and PP2A.
  • These inhibitors demonstrated tumor-promoting activity in multiple organs (skin, stomach, liver) when initiated with different carcinogens.
  • Sustained protein phosphorylation due to PP1 and PP2A inhibition was identified as the key mechanism.

Conclusions:

  • Inhibition of protein phosphatases 1 and 2A represents a general mechanism of tumor promotion.
  • This mechanism is applicable to various organs and carcinogen types.
  • The findings support the role of endogenous tumor promoters in human cancer development.

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