Extracellular signal-regulated kinase phosphorylation due to menadione-induced arylation mediates growth inhibition of pancreas cancer cells

Osada, Shinji; Sakashita, Fumio; Hosono, Yosiki; Nonaka, Kenichi; Tokuyama, Yasuharu; Tanaka, Hidenori; Sasaki, Yoshiyuki; Tomita, Hiroyuki; Komori, Shuji; Matsui, Shinji; Takahashi, Tsuyoshi

doi:10.1007/s00280-007-0610-9

Cited by 21 publications

(15 citation statements)

References 27 publications

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“…It has been shown to promote cell survival under some conditions (Cheung and Slack, 2004), but to increase the sensitivity to oxidative stress under other conditions. Inhibition of ERK abrogates cell death induced by H 2 O 2 in pancreatic cancer cells (Osada et al, 2007) and protects against glutamate-induced neuronal death (Satoh et al, 2000). Furthermore, certain drugs protect neurons partly by inhibiting ERK activation (Xu et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

SirT1 Inhibition Reduces IGF-I/IRS-2/Ras/ERK1/2 Signaling and Protects Neurons

et al. 2008

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Sirtuins have been shown to protect cells and delay aging, but our laboratory showed that S. cerevisiae Sir2 can also increase stress sensitivity and limit life span extension. Here we provide evidence for a role of the mammalian Sir2 ortholog SirT1 in the activation of a pathway that sensitizes neurons to oxidative damage. SirT1-inhibition increased acetylation and decreased phosphorylation of IRS-2, reduced Ras activation and reduced ERK1/2 phosphorylation suggesting that SirT1 may enhance IGF-I signaling in part by deacetylating IRS-2. Either of the inhibition of SirT1 or of Ras/ERK1/2 were associated with resistance to oxidative damage. Although both markers of oxidized proteins and lipids were reduced in the brain of old SirT1 deficient mice, the life span of the homozygote knock out mice was shorter under both normal and calorie restricted conditions. These results are consistent with findings in S. cerevisiae and other model organisms suggesting that mammalian sirtuins can play both protective and pro-aging roles.

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Section: Discussionmentioning

confidence: 99%

SirT1 Inhibition Reduces IGF-I/IRS-2/Ras/ERK1/2 Signaling and Protects Neurons

et al. 2008

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“…ERK activation has been shown to promote cell survival under some conditions [29, 30], but it increases the sensitivity to oxidative stress under other conditions [31]. Inhibition of ERK abrogates cell death induced by H 2 O 2 in pancreatic cancer cells [32] and protects against glutamate-induced neuronal death [33]. In the present context, it is noteworthy that fibroblasts from Snell dwarf mice, though resistant to many forms of lethal injury [11, 12], are actually more susceptible than control cells to the lethal effects of agents (tunicamycin and thapsigargin) that induce apoptosis through the ER (endoplasmic reticulum) stress pathway [34].…”

Section: Discussionmentioning

confidence: 99%

Fibroblasts from long-lived mutant mice show diminished ERK1/2 phosphorylation but exaggerated induction of immediate early genes

Sun

Steinbaugh

Masternak

et al. 2009

Free Radical Biology and Medicine

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Skin-derived fibroblasts from long-lived mutant mice, including the Snell dwarf mice and mice defective in growth hormone receptor ("GHRKO"), are resistant to death induced by oxidative stresses or by UV light, but the molecular mechanism for their stress resistance is unknown. The present study showed that phosphorylation of the stress-activated protein kinases ERK1/2 induced by peroxide, cadmium, or paraquat was attenuated in cells from these mice. Induction of ERK phosphorylation by UV light was not altered in the Snell dwarf cells, and neither JNK nor p38 kinases showed increased phosphorylation in response to any of the stresses tested. Surprisingly, stressinduced elevation of mRNA for certain Immediate Early Genes (egr-1 and fos) was higher in Snellderived cells than in control cells, despite the evidence of lower ERK phosphorylation. Thus cells from Snell dwarf mice differ from controls in two ways: (a) lower induction of ERK1/2 phosphorylation, and (b) increased expression of some ERK-dependent IEGs. These alterations in kinase pathways may contribute to the resistance of these cells to lethal injury.

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“…These keratinocytes are more sensitized to apoptosis upon deprivation of EGF and insulin, implicating that Erk1/2 activation though Tiam1 and ROS is required for cell survival of skin cancer [69]. In contrast, in human pancreatic cancer and glioma cells, activation of Erk1/2 upon treatment with exogenous H 2 O 2 triggers cell death and this probably is due to the high basal level of ROS in these cancer cells [72–76]. In line with these in vitro data is an in vivo study showning that ROS-mediated increase of Erk1/2 activation loop phosphorylation suppresses the growth of pancreatic tumor cell xenografts[77].…”

Section: Signaling Pathways Regulated By Ros In Cancermentioning

confidence: 99%

Reactive oxygen species in cancer

Liou

Störz

2010

Free Radical Research

2,870

2,018

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Elevated rates of reactive oxygen species (ROS) have been detected in almost all cancers, where they promote many aspects of tumor development and progression. However, tumor cells also express increased levels of antioxidant proteins to detoxify from ROS, suggesting that a delicate balance of intracellular ROS levels is required for cancer cell function. Further, the radical generated, the location of its generation, as well as the local concentration is important for the cellular functions of ROS in cancer. A challenge for novel therapeutic strategies will be the fine tuning of intracellular ROS signaling to effectively deprive cells from ROS-induced tumor promoting events, towards tipping the balance to ROS-induced apoptotic signaling. Alternatively, therapeutic antioxidants may prevent early events in tumor development, where ROS are important. However, to effectively target cancer cells specific ROS-sensing signaling pathways that mediate the diverse stress-regulated cellular functions need to be identified. This review discusses the generation of ROS within tumor cells, their detoxification, their cellular effects, as well as the major signaling cascades they utilize, but also provides an outlook on their modulation in therapeutics.

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Extracellular signal-regulated kinase phosphorylation due to menadione-induced arylation mediates growth inhibition of pancreas cancer cells

Abstract: VK3-induced ERK phosphorylation occurs by a different mechanism from oxidative stress, and it might have an important role to induce growth inhibition.

Cited by 21 publications

References 27 publications

SirT1 Inhibition Reduces IGF-I/IRS-2/Ras/ERK1/2 Signaling and Protects Neurons

SirT1 Inhibition Reduces IGF-I/IRS-2/Ras/ERK1/2 Signaling and Protects Neurons

Fibroblasts from long-lived mutant mice show diminished ERK1/2 phosphorylation but exaggerated induction of immediate early genes

Reactive oxygen species in cancer

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