Carbonyl Reductase 1 Offers a Novel Therapeutic Target to Enhance Leukemia Treatment by Arsenic Trioxide

Jang, Miran; Kim, Yeonghwan; Won, Hyeran; Lim, Sung‐Jig; K.R, Jyothi; Dashdorj, Amarjargal; Min, Yoo Hong; Kim, Si-Young; Shokat, Kevan M.; Ha, Joohun; Kim, Sung Soo

doi:10.1158/0008-5472.can-12-1110

Cited by 25 publications

(23 citation statements)

References 46 publications

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“…Some studies showed that As 2 O 3 achieve anti-tumor activity by inhibiting AP-1 [4,23]. However, there are different reports that As 2 O 3 stimulated the activity of the AP-1 in cultured human fibroblasts [24] and acute promyelocytic leukemia [25]. Paradoxical results may be existed in various cells treated by As 2 O 3 because many arsenic properties share in both anti-cancer and pro-cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Since As 2 O 3 induces apoptosis of various cancer cell lines [6,23,[25][26][27][28][29][30][31], including cervical cancer cell lines expressing or not expressing HPV [4,[7][8][9], it is obvious that the mechanisms of As 2 O 3 induced apoptosis are different in various cancer cell lines. In the study, only cervical cancer cell lines were used for investigation.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Arsenic trioxide inhibits cell proliferation and human papillomavirus oncogene expression in cervical cancer cells

Wang¹,

Gao²,

Zheng³

2014

Biochemical and Biophysical Research Communications

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Arsenic trioxide inhibits cell proliferation and human papillomavirus oncogene expression in cervical cancer cells

Wang¹,

Gao²,

Zheng³

2014

Biochemical and Biophysical Research Communications

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“…These drug metabolites display 2-4-fold reduction in cytotoxicity compared with their parental drugs because this conversion is a significant step in the detoxification. Additionally, CBR1 up-regulation can eliminate ROS induced by cisplatin or arsenic trioxide (As 2 O 3 ) in protection against drug-induced damage to leukemia cells (Jang et al, 2012;Tak et al, 2011), and this effect can be attributed to CBR1-mediated detoxication of the reactive carbonyls by reducing the carbonyl groups of drugs to alcohol because reactive carbonyls have the ability to up-regulate the expression of the main enzymes that produces ROS. These evidences demonstrated that CBR1 could be considered as a potential therapeutic target to improve the efficacy of these anticancer agents.…”

Section: Cbrsmentioning

confidence: 99%

Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters

Bai

Chen

Hou

et al. 2016

Drug Metabolism Reviews

135

105

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Chemoresistance is a disturbing barrier in cancer therapy, which always results in limited therapeutic options and unfavorable prognosis. Nuclear factor E2-related factor 2 (NRF2) controls the expression of genes encoding cytoprotective enzymes and transporters that protect against oxidative stress and electrophilic injury to maintain intrinsic redox homeostasis. However, recent studies have demonstrated that aberrant activation of NRF2 due to genetic and/or epigenetic mutations in tumor contributes to the high expression of phase I and phase II drug-metabolizing enzymes, phase III transporters, and other cytoprotective proteins, which leads to the decreased therapeutic efficacy of anticancer drugs through biotransformation or extrusion during chemotherapy. Therefore, a better understanding of the role of NRF2 in regulation of these enzymes and transporters in tumors is necessary to find new strategies that improve chemotherapeutic efficacy. In this review, we summarized the recent findings about the chemoresistance-promoting role of NRF2, NRF2-regulated phase I and phase II drug-metabolizing enzymes, phase III drug efflux transporters, and other cytoprotective genes. Most importantly, the potential of NRF2 was proposed to counteract drug resistance in cancer treatment.

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“…Among the candidates of RACK1-interacting proteins obtained, CBR1 was notable due to its close association with ROS. CBR1 was considered to be a ROS suppressor, as it had been reported to protect cells from cytotoxic drug-triggered cell death in doxorubicin-treated HCC cells and As 2 O 3 -treated leukemia cells (4,18). Therefore, the functions of CBR1 were investigated in TNF-α-treated SMMC7721 cells.…”

Section: Rack1 Suppresses Tnf-α-induced Cell Death Via Cbr1mentioning

confidence: 99%

“…A combination of co-immunoprecipitation (co-IP) and mass spectrometry analysis indicated that carbonyl reductase 1 (CBR1), a ubiquitous nicotinamide adenine dinucleotide phosphate-dependent enzyme, acts as a RACK1-interacting partner in HCC cells. CBR1 has been reported to provide protection from ROS-induced cellular damage in HCC and leukemia (4,18), which suggests that CBR1 serves a role in cellular anti-oxidation. In the present study, it was reported that overexpression of exogenous CBR1 in HCC cells reverses enhanced cell death upon silencing of endogenous RACK1, which indicated that RACK1 may have a pivotal role in sustaining the protein stability of CBR1.…”

Section: Introductionmentioning

confidence: 99%

RACK1 promotes hepatocellular carcinoma cell survival via CBR1 by suppressing TNF-α-induced ROS generation

Zhou¹,

Cao²,

Zhao³

et al. 2016

Oncology Letters

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Abstract. It has been reported that intracellular accumulation of reactive oxygen species (ROS) has a significant role in tumor necrosis factor (TNF)-α-induced cell apoptosis and necrosis; however, the key molecules regulating ROS generation remain to be elucidated. The present study reports that knockdown of endogenous receptor for activated C kinase 1 (RACK1) increases the intracellular ROS level following TNF-α or H 2 O 2 stimulation in human hepatocellular carcinoma (HCC) cells, leading to promotion of cell death. Carbonyl reductase 1 (CBR1), a ubiquitous nicotinamide adenine dinucleotide phosphate-dependent enzyme, is reported to protect cells from ROS-induced cell damage. The present study reports that RACK1 is a regulator of CBR1 that interacts with and sustains the protein stability of CBR1. Overexpression of CBR1 reverses the enhanced cell death due to RACK1 knockdown. Taken together, the results of the present study suggest that RACK1 protects HCC cells from TNF-α-induced cell death by suppressing ROS generation through interacting with and regulating CBR1. IntroductionEscape from tumor necrosis factor (TNF)-α-induced cell apoptosis and necrosis is of importance in tumor development (1-3).This process is regulated by a number of intracellular signaling pathways, including c-jun N-terminal kinase (JNK) and IκB kinase (IKK), as well as reactive oxygen species (ROS) (4,5). Extensive studies have indicated that reduced levels of oxidant stress and ROS promote malignant transformation and oncogenic growth in hepatocellular carcinoma (HCC) cells (6-9). However, the key molecules regulating ROS in HCC remain to be elucidated. It has been reported that scaffolding protein receptor for activated C kinase 1 (RACK1) enhances JNK activation in HCC, leading to promotion of the malignant growth of HCC (10). Therefore, it may be assumed that RACK1 affects other aspects of HCC. RACK1 was originally identified to bind and activate protein kinase C and is now recognized as a multi-functional scaffold protein (11,12). Evidence has indicated that RACK1 protects from oxidative stress-induced cell death in various types of cells, including fission yeasts (13), shrimp cells (14), neurons (15), HeLa cells (16) and HL60 cells (17). However, such a role for RACK1 has not been reported in HCC cells to the best of our knowledge. In the present study, it was demonstrated that RACK1 knockdown leads to increased cell death in TNF-α-treated HCC cells in the presence of cycloheximide (CHX), a protein synthesis inhibitor. Subsequently, it was observed that RACK1 knockdown promotes intracellular ROS accumulation upon TNF-α or H 2 O 2 stimulation. A combination of co-immunoprecipitation (co-IP) and mass spectrometry analysis indicated that carbonyl reductase 1 (CBR1), a ubiquitous nicotinamide adenine dinucleotide phosphate-dependent enzyme, acts as a RACK1-interacting partner in HCC cells. CBR1 has been reported to provide protection from ROS-induced cellular damage in HCC and leukemia (4,18), which suggests that CBR1 serves a role in c...

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Carbonyl Reductase 1 Offers a Novel Therapeutic Target to Enhance Leukemia Treatment by Arsenic Trioxide

Cited by 25 publications

References 46 publications

Arsenic trioxide inhibits cell proliferation and human papillomavirus oncogene expression in cervical cancer cells

Arsenic trioxide inhibits cell proliferation and human papillomavirus oncogene expression in cervical cancer cells

Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters

RACK1 promotes hepatocellular carcinoma cell survival via CBR1 by suppressing TNF-α-induced ROS generation

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