Mitogen-activated protein kinases mediate arsenic-induced down-regulation of survivin in human lung adenocarcinoma cells

Cheng, Ya-Hsin; Chang, Louis W.; Tsou, Tsui‐Chun

doi:10.1007/s00204-005-0045-1

Cited by 36 publications

(22 citation statements)

References 34 publications

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“…Cells were transfected with siRNA duplexes (200 nmol/L) by using Lipofectamine 2000 (Invitrogen) for 24 hours. Plasmids transfection of MKK6E (a constitutively active form of MKK6) and HA-p38 MAPK were achieved as previously described (23,24). Exponentially growing human lung cancer cells (10 6 ) were plated for 18 hours, and then MKK6E expression vectors were transfected into A549 or H1975 cells using Lipofectamine (Invitrogen).…”

Section: Transfection With Short Interfering Rna or Mkk6e And Ha-p38 mentioning

confidence: 99%

Inhibition of p38 MAPK-Dependent Excision Repair Cross-Complementing 1 Expression Decreases the DNA Repair Capacity to Sensitize Lung Cancer Cells to Etoposide

Tsai

Weng

Chen

et al. 2012

Molecular Cancer Therapeutics

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Etoposide (VP-16), a topoisomerase II inhibitor, is an effective anticancer drug currently used for the treatment of a wide range of cancers. Excision repair cross-complementary 1 (ERCC1) is a key protein involved in the process of nucleotide excision repair. High level of ERCC1 expression in cancers is associated with resistance to DNA damage-based chemotherapy. In this study, the effects of p38 mitogenactivated protein kinase (MAPK) signal on the ERCC1 expression induced by etoposide in non-small cell lung cancer (NSCLC) cell lines was investigated. Etoposide increased phosphorylated MAPK kinase 3/6 (MKK3/6)-p38 MAPK and ERCC1 protein and mRNA levels in A549 and H1975 cells. Moreover, SB202190, a p38 inhibitor, or knockdown of p38 expression by specific short interfering RNA (siRNA) significantly decreased the etoposide-induced ERCC1 protein levels and DNA repair capacity in etoposide-exposed NSCLC cells. Enhancement of p38 activation by constitutively active MKK6 (MKK6E) increased ERCC1 protein levels. Specific inhibition of ERCC1 by siRNA significantly enhanced the etoposide-induced cytotoxicity and hypoxanthine guanine phosphoribosyltransferase (hprt) gene mutation rate. Moreover, the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) could decrease the etoposideinduced p38 MAPK-mediated ERCC1 expression and augment the cytotoxic effect and growth inhibition by etopsoside. 17-AAG and etoposide-induced synergistic cytotoxic effect and DNA repair capacity decrease could be abrogated in lung cancer cells with MKK6E or HA-p38 MAPK expression vector transfection. Our results suggest that in human NSCLC cells, ERCC1 is induced by etoposide through the p38 MAPK pathway, and this phenomenon is required for NSCLC survival and resistant DNA damage.

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Section: Transfection With Short Interfering Rna or Mkk6e And Ha-p38 mentioning

confidence: 99%

Inhibition of p38 MAPK-Dependent Excision Repair Cross-Complementing 1 Expression Decreases the DNA Repair Capacity to Sensitize Lung Cancer Cells to Etoposide

Tsai

Weng

Chen

et al. 2012

Molecular Cancer Therapeutics

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“…Activation of p38 MAPK has been shown to associate with ATO-induced apoptosis of human leukemic cell lines, U937 and K562 cells (31,32,35). To determine whether or not p38 MAPK is required for ATO-induced apoptosis of NB4 cells, the cells were untreated or treated with ATO (10 M) in the absence (DMSO alone) or presence of the p38 MAPK inhibitor SB203580 (10 M), and 24 h after incubation, apoptotic cells were scored (see "Experimental Procedures").…”

Section: Activation Of Chk2 and P38 Mapk In An Aplmentioning

confidence: 99%

“…It has been shown that p38 MAPK stimulates p53 in response to various stress agents, including UV irradiation and anticancer drugs, and regulates both activation of p53-mediated transcription and p53-dependent apoptosis (29,30). ATO is known to activate p38 MAPK in various neoplastic cell lines, suggesting a role for this pathway in the regulation of ATO-induced responses in malignant cells (31)(32)(33)(34)(35).…”

mentioning

confidence: 99%

Arsenic Trioxide Augments Chk2/p53-mediated Apoptosis by Inhibiting Oncogenic Wip1 Phosphatase

Yoda

Toyoshima

Watanabe

et al. 2008

Journal of Biological Chemistry

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The oncogenic Wip1 phosphatase (PPM1D) is induced upon DNA damage in a p53-dependent manner and is required for inactivation or suppression of DNA damage-induced cell cycle checkpoint arrest and of apoptosis by dephosphorylating and inactivating phosphorylated Chk2, Chk1, and ATM kinases. It has been reported that arsenic trioxide (ATO), a potent cancer chemotherapeutic agent, in particular for acute promyelocytic leukemia, activates the Chk2/p53 pathway, leading to apoptosis. ATO is also known to activate the p38 MAPK/p53 pathway. Here we show that phosphatase activities of purified Wip1 toward phosphorylated Chk2 and p38 in vitro are inhibited by ATO in a dose-dependent manner. Furthermore, DNA damageinduced phosphorylation of Chk2 and p38 in cultured cells is suppressed by ectopic expression of Wip1, and this Wip1-mediated suppression can be restored by the presence of ATO. We also show that treatment of acute promyelocytic leukemia cells with ATO resulted in induction of phosphorylation and activation of Chk2 and p38 MAPK, which are required for ATO-induced apoptosis. Importantly, this ATO-induced activation of Chk2/p53 and p38 MAPK/p53 apoptotic pathways can be enhanced by siRNA-mediated suppression of Wip1 expression, further indicating that ATO inhibits Wip1 phosphatase in vivo. These results exemplify that Wip1 is a direct molecular target of ATO.

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“…Disulfide-linked PML or PML-RAR␣ multimers form nuclear matrix-associated nuclear bodies and become sumoylated and then degraded (32,33). In addition to PML-RAR␣, several other proteins with a high content of cysteine residues and vicinal thiol groups are also targets of arsenic, such as AML1/MDS1/EVI1 protein produced from a fusion gene generated by a t(3;21)(q26;q22) translocation in chronic myelogenous leukemia (34), Gli2 transcriptional effector in the Hedgehog pathway (35), AKT protein (36), BCR/ABL protein produced from a fusion gene generated by a t(9;22) chromosomal translocation in chronic myelogenous leukemia (37), and survivin (38).…”

mentioning

confidence: 99%

Mutant p53 Protein Is Targeted by Arsenic for Degradation and Plays a Role in Arsenic-mediated Growth Suppression

Yan¹,

Zhang²,

Zhang

et al. 2011

Journal of Biological Chemistry

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p53 is frequently mutated in tumor cells, and mutant p53 is often highly expressed due to its increased half-life. Thus, targeting mutant p53 for degradation might be explored as a therapeutic strategy to manage tumors that are addicted to mutant p53 for survival. Arsenic trioxide, a drug for patients with acute promyelocytic leukemia, is found to target and degrade a class of proteins with high levels of cysteine residues and vicinal thiol groups, such as promyelocytic leukemia protein (PML) and PML-retinoic acid receptor ␣ fusion protein. Interestingly, wild type p53 is accumulated in cells treated with arsenic compounds, presumably due to arsenic-induced oxidative stresses. In this study, we found that wild type p53 is induced by arsenic trioxide in tumor cells, consistent with published studies. In contrast, we found that arsenic compounds degrade both endogenous and ectopically expressed mutant p53 in time-and dose-dependent manners. We also found that arsenic trioxide decreases the stability of mutant p53 protein through a proteasomal pathway, and blockage of mutant p53 nuclear export can alleviate the arsenic-induced mutant p53 degradation. Furthermore, we found that knockdown of endogenous mutant p53 sensitizes, whereas ectopic expression of mutant p53 desensitizes, tumor cells to arsenic treatment. Taken together, we found that mutant p53 is a target of arsenic compounds, which provides an insight into exploring arsenic compound-based therapy for tumors harboring a mutant p53.

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Mitogen-activated protein kinases mediate arsenic-induced down-regulation of survivin in human lung adenocarcinoma cells

Cited by 36 publications

References 34 publications

Inhibition of p38 MAPK-Dependent Excision Repair Cross-Complementing 1 Expression Decreases the DNA Repair Capacity to Sensitize Lung Cancer Cells to Etoposide

Inhibition of p38 MAPK-Dependent Excision Repair Cross-Complementing 1 Expression Decreases the DNA Repair Capacity to Sensitize Lung Cancer Cells to Etoposide

Arsenic Trioxide Augments Chk2/p53-mediated Apoptosis by Inhibiting Oncogenic Wip1 Phosphatase

Mutant p53 Protein Is Targeted by Arsenic for Degradation and Plays a Role in Arsenic-mediated Growth Suppression

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