Selective GSK-3β inhibitors attenuate the cisplatin-induced cytotoxicity of auditory cells

Park, Hee-Je; Kim, Hyungjin; Bae, Gi‐Sang; Seo, Sang-Wan; Kim, Doyun; Jung, Won Yong; Kim, Min-Sun; Song, Mi-Young; Kim, Min Jung; Kwon, Kang‐Beom; Hwang, Sung-Yeon; Song, Ho‐Joon; Park, Cheung-Seog; Park, Raekil; Chong, Myong-Soo; Park, Sung‐Joo

doi:10.1016/j.heares.2009.08.001

Cited by 42 publications

(40 citation statements)

References 37 publications

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“…Specific ABR wave parameters like interpeak latencies between P2 and P1 are thought to be a reflection of the myelination status [58], [59], while changes in P3 and P4 interpeak latencies are also suggestive of impairments in synapse maturation [60], [61], [62], [63]. Measurements of Distortion-Product of Otoacoustic Emissions (DPOAE) can be used to exclude impairments that are due to a peripheral loss of hair cell function that would also affect the general neural output [64], [65], [66], [67].…”

Section: Resultsmentioning

confidence: 99%

Identifying a Window of Vulnerability during Fetal Development in a Maternal Iron Restriction Model

et al. 2011

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It is well acknowledged from observations in humans that iron deficiency during pregnancy can be associated with a number of developmental problems in the newborn and developing child. Due to the obvious limitations of human studies, the stage during gestation at which maternal iron deficiency causes an apparent impairment in the offspring remains elusive. In order to begin to understand the time window(s) during pregnancy that is/are especially susceptible to suboptimal iron levels, which may result in negative effects on the development of the fetus, we developed a rat model in which we were able to manipulate and monitor the dietary iron intake during specific stages of pregnancy and analyzed the developing fetuses. We established four different dietary-feeding protocols that were designed to render the fetuses iron deficient at different gestational stages. Based on a functional analysis that employed Auditory Brainstem Response measurements, we found that maternal iron restriction initiated prior to conception and during the first trimester were associated with profound changes in the developing fetus compared to iron restriction initiated later in pregnancy. We also showed that the presence of iron deficiency anemia, low body weight, and changes in core body temperature were not defining factors in the establishment of neural impairment in the rodent offspring.Our data may have significant relevance for understanding the impact of suboptimal iron levels during pregnancy not only on the mother but also on the developing fetus and hence might lead to a more informed timing of iron supplementation during pregnancy.

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Section: Resultsmentioning

confidence: 99%

Identifying a Window of Vulnerability during Fetal Development in a Maternal Iron Restriction Model

et al. 2011

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“…This idea is supported by evidence that TNF α is produced by OHCs, supporting cells, and fibrocytes in the spiral ligament following a variety of insults including noise exposure, excessive vibration, and treatment with cisplatin. 28, 29, 30, 31, 32 …”

Section: Discussionmentioning

confidence: 99%

Receptor-interacting protein kinases modulate noise-induced sensory hair cell death

Zheng

Chen

2014

Cell Death Dis

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Receptor-interacting protein (RIP) kinases promote the induction of necrotic cell death pathways. Here we investigated signaling pathways in outer hair cells (OHCs) of adult male CBA/J mice exposed to noise that causes permanent threshold shifts, with a particular focus on RIP kinase-regulated necroptosis. One hour after noise exposure, nuclei of OHCs in the basal region of the cochlea displayed both apoptotic and necrotic features. RIP1 and RIP3 protein levels increased and caspase-8 was activated. Treatment with pan-caspase inhibitor ZVAD blocked the activation of caspase-8 and reduced the number of apoptotic nuclei, while increasing levels of RIP1, RIP3, and necrotic OHCs. Conversely, treatment with necrosis inhibitor necrostatin-1 (Nec-1) or RIP3 siRNA (siRIP3) diminished noise-induced increases in RIP1 and RIP3, and decreased necrotic OHC nuclei. This treatment also increased the number of apoptotic nuclei without increasing activation of caspase-8. Consistent with the elevation of levels of RIP1 and RIP3, noise-induced active AMPKα levels increased with ZVAD treatment, but decreased with Nec-1 and siRIP3 treatment. Furthermore, treatment with siRIP3 did not alter the activation of caspase-8, but instead increased activation of caspase-9 and promoted endonuclease G translocation into OHC nuclei. Finally, auditory brainstem response functional measurements and morphological assessment of OHCs showed that ZVAD treatment reduces noise-induced deficits. This protective function is potentiated when combined with siRIP3 treatment. In conclusion, noise-induced OHC apoptosis and necrosis are modulated by caspases and RIP kinases, respectively. Inhibition of either pathway shifts the prevalence of OHC death to the alternative pathway.

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“…There are two GSK3 isoforms in mammalians that are encoded by distinct genes: GSK3a and GSK3b. GSK3b has differential roles in the regulation of transcriptional activation and apoptosis (Park et al, 2009;Yun et al, 2009). GSK3b is recognized as much potential tumor suppressor as GSK3 phosphorylated pro-oncogenic molecules such as c-Jun, c-Myc, CREB, CCND1, and b-catenin.…”

Section: Discussionmentioning

confidence: 99%

The Epigenetically Regulated Effects of Wnt Antagonists on the Expression of Genes in the Apoptosis Pathway in Human Bladder Cancer Cell Line (T24)

Varol

Konac

Onen

et al. 2014

DNA and Cell Biology

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The epigenetic suppression of Wnt antagonists (sFRPs, DKKs, and WIF-1) causes the activation of both β-catenin and target genes, which play an important role in cell proliferation, metastasis, and angiogenesis. This study is aimed to investigate, on transcriptional and protein levels, the synergic effects of unaccompanied and/or combined use of 5-aza-2'-deoxycytidine (DAC, 5-aza-dC), trichostatin A (TSA), and gemcitabine+cisplatin chemotherapeutic agents on the apoptotic pathway of human bladder cancer cell line T24. The anti-tumor effects of gemcitabine (0-500 nM), cisplatin (0-10 μM), DAC (10 μM), and TSA (300 nM) alone and/or together on T24 cells were determined by WST-1. ELISA method was used to analyze the effects of unaccompanied and combined use of gemcitabine+cisplatin, DAC, and TSA on cell proliferation and determine the cytotoxic and apoptotic dosages at the level of H3 histone acetylation. Methylation-specific PCR was used to evaluate methylation profiles of Wnt antagonist gene (WIF-1). In the case of unaccompanied and/or combined use of specified drugs, the variations in the expression levels of CTNNB1, GSK3β, c-MYC, CCND1, CASP-3, CASP-8, CASP-9, BCL2L1, and WIF-1 genes were determined by quantitative real-time PCR. Our results indicate that through inhibition of DNA methylation, expression of β-catenin and Wnt antagonist re-activation and expressions of canonical Wnt/β-catenin pathway target genes, c-myc and cyclin D1 (CCND1), have decreased. In addition, DAC, TSA, and gemcitabine+cisplatin combination caused an increase in GSK3β mRNA levels, which in turn significantly decreased CCND1 mRNA levels. Moreover, BCL2L1, an anti-apoptotic gene, was downregulated significantly. Meanwhile, both CASP-3 mRNA and active caspase-3 protein levels increased with respect to control (p<0.01). The results revealed that use of quadruplicate gemcitabine+cisplatin+DAC+TSA combination led to a reduced inhibition of canonical Wnt/β-catenin pathway and reduced cell proliferation. Our findings may offer a new approach to consider in the treatment of bladder cancer.

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Selective GSK-3β inhibitors attenuate the cisplatin-induced cytotoxicity of auditory cells

Cited by 42 publications

References 37 publications

Identifying a Window of Vulnerability during Fetal Development in a Maternal Iron Restriction Model

Identifying a Window of Vulnerability during Fetal Development in a Maternal Iron Restriction Model

Receptor-interacting protein kinases modulate noise-induced sensory hair cell death

The Epigenetically Regulated Effects of Wnt Antagonists on the Expression of Genes in the Apoptosis Pathway in Human Bladder Cancer Cell Line (T24)

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