Inositol hexakisphosphate blocks tumor cell growth by activating apoptotic machinery as well as by inhibiting the Akt/NFκB-mediated cell survival pathway

Sandra Ferry, Miho Matsuda, Hiroki Yoshida, Masato Hirata

Research output: Contribution to journalReview article

88 Citations (Scopus)

Abstract

It has been reported that inositol hexakisphosphate (InsP6, phytic acid), a natural product, has an anticancer role. However, there is inadequate information regarding the mechanism by which InsP6 exerts anticancer actions, and the effect requires relatively high concentration of the agent, both of which hinders the usage of InsP6 as an anticancer drug. In the present study, we investigated the mechanism by Which InsP6 acts as an anticancer agent, and tried to reduce the concentration of effective InsP6. Treatment of HeLa cells with InsP6 at 1 mM induced apoptosis, as assessed by counting the cell number, and by Hoechst and TUNEL staining. This is probably mediated by intracellular InsP6 itself and/or the dephosphorylated forms of metabolized InsP6, because incubation of HeLa cells with [3H]InsP6 produces dephosphorylated forms such as InsP4 and InsP5. Induction of apoptosis by InsP6 was examined in two ways: inhibition of cell survival signaling and direct induction of apoptosis. Treatment of HeLa cells with tumor necrosis factor (TNF) or insulin stimulated the Akt-nuclear factor κB (NFκB) pathway, a cell survival signal, which involves the phosphorylation of Akt and IκB, nuclear translocation of NFκB and NFκB-luciferase transcription activity. InsP6 blocked all these cellular events, but phosphatidylinositol 3-kinase activity was not affected. As well as inhibiting the Akt-NFκB pathway, InsP6 itself caused mitochondrial permeabilization, followed by cytochrome c release, which later caused activation of the apoptotic machinery, caspase 9, caspase 3 and poly (ADP-ribose) polymerase. When InsP6 was applied together with histone, the effective concentration to induce apoptosis was ∼10-fold lower. These results revealed that extracellularly applied InsP6 directly activates the apoptotic machinery as well as inhibits the cell survival signaling, probably by the intracellular delivery followed by a dephosphorylation.

Original languageEnglish
Pages (from-to)2031-2041
Number of pages11
JournalCarcinogenesis
Volume23
Issue number12
DOIs
Publication statusPublished - Dec 1 2002

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Phytic Acid
Cell Survival
HeLa Cells
Apoptosis
Growth
Neoplasms
Phosphatidylinositol 3-Kinase
Poly(ADP-ribose) Polymerases
Caspase 9
In Situ Nick-End Labeling
Cytochromes c
Biological Products
Luciferases
Caspase 3
Antineoplastic Agents
Histones
Tumor Necrosis Factor-alpha
Cell Count
Phosphorylation
Insulin

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Inositol hexakisphosphate blocks tumor cell growth by activating apoptotic machinery as well as by inhibiting the Akt/NFκB-mediated cell survival pathway. / Ferry, Sandra; Matsuda, Miho; Yoshida, Hiroki; Hirata, Masato.

In: Carcinogenesis, Vol. 23, No. 12, 01.12.2002, p. 2031-2041.

Research output: Contribution to journalReview article

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