Palytoxin is a non-12-<i>O</i>-tetradecanoylphorbol-13-acetate type tumor promoter in two-stage mouse skin carcinogenesis

Fujiki, Hirota; Suganuma, Masami; Nakayasu, Michie; Hakii, Hiromi; Horiuchi, Takahiko; Takayama, Seiji; Sügimura, Takashi

doi:10.1093/carcin/7.5.707

Cited by 98 publications

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“…The initial signals stimulated by palytoxin differ significantly from those stimulated by TPA (5)(6)(7). Palytoxin is a large (M r 2,681), water-soluble polyalcohol isolated from zoanthids (genus Palythoa), which are closely related to sea anemones (8).…”

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confidence: 96%

Mitogen-activated Protein Kinase Phosphatase-3 Is a Tumor Promoter Target in Initiated Cells That Express Oncogenic Ras

Warmka¹,

Mauro

Wattenberg³

2004

Journal of Biological Chemistry

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We have capitalized on the unique properties of the skin tumor promoter palytoxin, which does not activate protein kinase C, to investigate alternative mechanisms by which major signaling molecules can be modulated during carcinogenesis. We report here that palytoxin activates extracellular signal-regulated kinase (ERK) through a novel mechanism that involves inactivation of an ERK phosphatase in keratinocytes derived from initiated mouse skin (308 cells). Use of U0126 revealed that palytoxin requires the ERK kinase MEK to stimulate ERK activity, although palytoxin did not activate MEK. We found that 308 keratinocytes highly express mitogen-activated protein kinase phosphatase-3 (MKP-3), which selectively inactivates ERK. Palytoxin induced the loss of MKP-3 in a manner that corresponded to increased ERK phosphorylation. Complementary studies showed that sustained expression of exogenous MKP-3 inhibited palytoxin-stimulated ERK activation. As is characteristic of initiated keratinocytes, 308 cells express activated H-Ras. To investigate whether expression of oncogenic Ras is key to palytoxin-stimulated ERK activation, we determined how palytoxin affected ERK and MKP-3 in MCF10A human breast epithelial cells and in H-ras MCF10A cells, which stably express activated H-Ras. Palytoxin did not affect ERK activity in MCF10A cells, which had no detectable MKP-3. Like 308 cells, H-ras MCF10A cells highly express MKP-3. Strikingly, palytoxin stimulated ERK activity and induced a corresponding loss of MKP-3 in H-ras MCF10A cells. These studies indicate that in initiated cells palytoxin unleashes ERK activity by down-regulating MKP-3, an ERK inhibitor, and further suggest that MKP-3 may be a vulnerable target in cells that express oncogenic Ras.

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confidence: 96%

Mitogen-activated Protein Kinase Phosphatase-3 Is a Tumor Promoter Target in Initiated Cells That Express Oncogenic Ras

Warmka¹,

Mauro

Wattenberg³

2004

Journal of Biological Chemistry

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“…8 Structure of palytoxin skin initiated with DMBA. The results presented a new concept, i.e., that tumor promotion on mouse skin can be induced by the TPA-type and non-TPA-type tumor promoters (Fujiki et al 1986).…”

Section: Palytoxinmentioning

confidence: 96%

“…Before going onto okadaic acid, we first showed palytoxin to be a unique tumor promoter belonging to the non-TPA-types (Fujiki et al 1986). Palytoxin was isolated from anthozoans of the genus Palythoa and is a water-soluble toxin with a long, partially unsaturated aliphatic chain with interspaced cyclic ethers (Uemura et al 1981; (Fig.…”

Section: Palytoxinmentioning

confidence: 99%

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Developmental Biology of Neoplastic Growth

Macieira‐Coelho¹

2005

Progress in Molecular and Subcellular Biology

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“…Palytoxin is a non-peptide water-soluble marine toxin that is a potent tumor promoter in the mouse skin carcinogenesis model (2)(3)(4). Many tumor-promoting compounds that are effective in the skin of carcinogen-initiated mice also produce an inflammatory reaction (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15).…”

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confidence: 99%

Loss of Cellular K+ Mimics Ribotoxic Stress

Iordanov

Magun

1998

Journal of Biological Chemistry

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The tumor promoter palytoxin has been found to activate the stress-activated protein kinase/c-Jun NH 2 -terminal kinase 1 (SAPK/JNK1), and it also potentiates, as demonstrated here, the p38/HOG1 mitogen-activated protein kinase and the upstream activator of SAPK/ JNK1, SEK1/MKK4. In search of possible mechanisms for both the cytotoxicity and the activation of stress kinases by palytoxin, we found that palytoxin is a potent inhibitor of cellular protein synthesis. To determine whether altered fluxes of either Na ؉ or K ؉ could be responsible for the effects of palytoxin on translation and on activation of SAPK/JNK1, cells were exposed to palytoxin in modified culture medium in which a major portion of the Na ؉ was replaced by either K ؉ or by choline ؉ . The substitution of Na ؉ by K ؉ strongly inhibited the ability of palytoxin both to inhibit protein translation and to activate SAPK/JNK1, whereas the substitution of Na ؉ by choline ؉ did not. These results suggest that palytoxin-induced efflux of cellular K ؉ mimics ribotoxic stress by provoking both translational inhibition and activation of protein kinases associated with cellular defense against stress.

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Palytoxin is a non-12-O-tetradecanoylphorbol-13-acetate type tumor promoter in two-stage mouse skin carcinogenesis

Cited by 98 publications

References 0 publications

Mitogen-activated Protein Kinase Phosphatase-3 Is a Tumor Promoter Target in Initiated Cells That Express Oncogenic Ras

Mitogen-activated Protein Kinase Phosphatase-3 Is a Tumor Promoter Target in Initiated Cells That Express Oncogenic Ras

Developmental Biology of Neoplastic Growth

Loss of Cellular K+ Mimics Ribotoxic Stress

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