Expression of heavy subunit of γ‐glutamylcysteine synthetase (γ‐GCSh) in human colorectal carcinoma

Tatebe, Shigeru; Unate, Hitoshi; Sinicrope, Frank A.; Sakatani, Takashi; Sugamura, Kenji; Makino, Masato; Ito, Hisao; Savaraj, Niramol; Kaibara, Nobuaki; Kuo, M. Tien

doi:10.1002/ijc.1574

Cited by 26 publications

(14 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…41 Indeed, frequent coexpression patterns of mRNAs for MRP1, g-GCS heavy subunit (g-GCSh) and GSTp were reported in a number of drug-resistant cell lines as well as human cancers. 42,43 It is suggested that the components of MRP1/GS-X pump can be coinduced by many cytotoxic agents. 44,45 Furthermore, it has been suggested that c-jun/AP-1 may be implicated in the regulation of expression of g-GCSh and GSTp 45,46 Collectively, in this study, g-GCSh and GSTp might be also induced by DOX via the JNKmediated pathway, leading to the increase in MRP1-mediated efflux.…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin induces expression of multidrug resistance-associated protein 1 in human small cell lung cancer cell lines by the c-jun N-terminal kinase pathway

et al. 2005

View full text Add to dashboard Cite

Multidrug resistance (MDR) is a major impediment to successful chemotherapy for lung cancer. Overexpression of multidrug resistance-associated protein 1 (MRP1) appears to be involved in MDR development in lung cancer cells. A number of chemotherapeutic agents including doxorubicin (DOX) were reported to induce MRP1 expression in human lung cancer cells. In our study, we investigated the mechanism by which DOX induces MRP1 expression in human small cell lung cancer (SCLC) cell lines, GLC4 and NCI-H82. These cells expressed MRP1 protein at low levels and were sensitive to DOX. Doxorubicin at 50 nM induced a marked increase in MRP1 expression in 24 hr, and stimulated c-jun N-terminal kinase (JNK) activity. Treatment with a JNK inhibitor, SP600125, significantly inhibited MRP1 induction. Furthermore, transfection with JNK1 and JNK2 antisense oligonucleotides markedly inhibited DOX-induced MRP1 expression. Chromatin immunoprecipitation assays revealed an enhanced recruitment of phosphorylated c-jun to the MRP1 promoter containing the AP-1 site upon DOX stimulation, which was inhibited by pretreatment with SP600125. Surprisingly, GLC4 cells exposed to DOX for 24 hr maintained increased MRP1 expression and resistance to DOX for at least 3 weeks. Pretreatment with SP600125 before DOX stimulation blocked the appearance of the MDR phenotype as well as MRP1 induction in GLC4 cells. These findings suggest that JNK activation may play an essential role for the induction of MRP1 protein in human SCLC cells by chemotherapeutic agents and that combined treatment of a JNK inhibitor with anticancer drugs may prevent the development of MDR by the abrogation of MRP1 induction. ' 2005 Wiley-Liss, Inc.Key words: MRP1; JNK; doxorubicin; small-cell lung cancer; multidrug resistance Small cell lung cancer (SCLC) accounts for 15-25% of all lung cancer patients.1,2 Although up to 90% of SCLC tumors initially respond to chemotherapy, patients with SCLC often relapse with multidrug resistant state. There are several types of multidrug resistance (MDR) to anticancer agents, and some of them were identified in human carcinoma cell lines in vitro. One of the mechanisms of MDR is decreased accumulation of drug within cells because of reduced inward transport or increased drug efflux, such as overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters. 3 P-glycoprotein (P-gp) that was cloned from KB-C 2.5 cells was the first ABC transporter identified. 4 Overexpression of P-gp has been detected in many multidrug resistant tumor cell lines and a variety of tumors from patients with both acquired and inherent drug resistance.5 Although P-gp is implicated in drug resistance in a number of tumor types, it is infrequently expressed in lung cancer cells. Another ABC transporter was cloned from the doxorubicin (DOX) resistant H69/AR SCLC cell line by Cole et al. 6 The transporter was designated as multidrug resistance-associated protein 1 (MRP1). The MRP family is now composed of 9 related ABC transporters that are able to transp...

show abstract

Section: Discussionmentioning

confidence: 99%

Doxorubicin induces expression of multidrug resistance-associated protein 1 in human small cell lung cancer cell lines by the c-jun N-terminal kinase pathway

et al. 2005

View full text Add to dashboard Cite

show abstract

“…68 Previous studies indicated that the cystine transport system X c 2 is involved in upregulation of intracellular GSH levels and drug resistance in ovarian cancer cell lines. 69 g-GCS has been reported to be upregulated in numerous cancers, including prostate cancer, 70 multiple myeloma, 71 nonsmall cell lung carcinoma, 72 colorectal carcinoma 73 and mesothelioma. 74 In the present study, no changes in expression levels of the catalytic subunit of this enzyme were observed during carcinogenesis (data not shown); however, activity levels were not measured.…”

Section: Discussionmentioning

confidence: 99%

Enhanced levels of glutathione and protein glutathiolation in rat tongue epithelium during 4‐NQO‐induced carcinogenesis

Huang¹,

Komninou²,

Kleinman³

et al. 2007

Intl Journal of Cancer

View full text Add to dashboard Cite

High glutathione (GSH) levels are commonly found in oral tumors and are thought to play an important role in tumorigenesis. While posttranslational binding of GSH to cellular proteins (protein glutathiolation) has recently been recognized as an important redoxsensitive regulatory mechanism, no data currently exist on this process during carcinogenesis. Our goal was to determine the effects of 4-nitroquinoline-N-oxide (4-NQO)-induced carcinogenesis on tongue levels of protein-bound and free GSH and related thiols in the rat. Male F-344 rats (6 weeks of age) were administered either 4-NQO (20 ppm) in drinking water or tap water alone (controls) for 8 weeks. Twenty-four weeks after cessation of 4-NQO, squamous cell carcinomas of the tongue were observed in all rats. The levels of both free and bound GSH in tumors, as well as in adjacent tissues, were 2-to 3-fold greater than in tongue epithelium from control rats (p < 0.05). Prior to tumor formation, at 8 weeks after cessation of 4-NQO, hyperplasia, dysplasia and carcinoma in situ were observed in 100%, 25% and 12.5% of 4-NQOtreated rats, respectively. At this early stage of carcinogenesis, levels of free and bound GSH were increased 50% compared with tongue tissues from control rats (p < 0.05). Glutathione disulfide (GSSG) levels were also 2-fold greater in tongue tissues from 4-NQO treated vs. control rats (p < 0.05). Altogether, these results suggest that protein glutathiolation, together with GSH and GSSG levels, are induced during oral carcinogenesis in the rat possibly as a result of enhanced levels of oxidative stress. ' 2006 Wiley-Liss, Inc.

show abstract

“…In human colorectal carcinomas, strong cytoplasmic staining for GCS heavy subunit was detected with a higher frequency than in adenoma and was significantly correlated with multidrug-resistance protein 1 expression (197). Another GSH-related enzyme, glutathione-S-transferase (GST), was elevated in colonic neoplasia compared with adjacent normal mucosa (129), but only a marginal increase in breast cancer was noted compared with normal adjacent tissues (44).…”

Section: Gsh Gsh-related Enzymes In Cancer Cellsmentioning

confidence: 99%

Redox Regulation by Intrinsic Species and Extrinsic Nutrients in Normal and Cancer Cells

McEligot

Yang²,

Meyskens³

2005

Annu. Rev. Nutr.

125

View full text Add to dashboard Cite

■ Abstract Cells in multicellular organisms are exposed to both endogenous oxidative stresses generated metabolically and to oxidative stresses that originate from neighboring cells and from other tissues. To protect themselves from oxidative stress, cells are equipped with reducing buffer systems (glutathione/GSH and thioredoxin/thioredoxin reductase) and have developed several enzymatic mechanisms against oxidants that include catalase, superoxide dismutase, and glutathione peroxidase. Other major extrinsic defenses (from the diet) include ascorbic acid, β-carotene and other carotenoids, and selenium. Recent evidence indicates that in addition to their antioxidant function, several of these redox species and systems are involved in regulation of biological processes, including cellular signaling, transcription factor activity, and apoptosis in normal and cancer cells. The survival and overall well-being of the cell is dependent upon the balance between the activity and the intracellular levels of these antioxidants as well as their interaction with various regulatory factors, including Ref-1, nuclear factor-κB, and activating protein-1.

show abstract

Expression of heavy subunit of γ‐glutamylcysteine synthetase (γ‐GCSh) in human colorectal carcinoma

Cited by 26 publications

References 37 publications

Doxorubicin induces expression of multidrug resistance-associated protein 1 in human small cell lung cancer cell lines by the c-jun N-terminal kinase pathway

Doxorubicin induces expression of multidrug resistance-associated protein 1 in human small cell lung cancer cell lines by the c-jun N-terminal kinase pathway

Enhanced levels of glutathione and protein glutathiolation in rat tongue epithelium during 4‐NQO‐induced carcinogenesis

Redox Regulation by Intrinsic Species and Extrinsic Nutrients in Normal and Cancer Cells

Contact Info

Product

Resources

About