Prognostic significance of amino-acid transporter expression (LAT1, ASCT2, and xCT) in surgically resected tongue cancer

Toyoda, Minoru; Kaira, Kyoichi; Ohshima, Yasuhiro; Ishioka, Noriko S.; Shino, Masato; Sakakura, Koichi; Takayasu, Yukihiro; Takahashi, Kengo; Tominaga, Hideyuki; Oriuchi, Noboru; Nagamori, Shushi; Kanai, Yoshikatsu; Oyama, Tetsunari; Chikamatsu, Kazuaki

doi:10.1038/bjc.2014.178

Cited by 110 publications

(132 citation statements)

References 27 publications

(77 reference statements)

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“…xCT is expressed in many types of malignancies and is associated with tumor growth and metastasis. It is also associated with resistance to chemotherapy and poor survival (13)(14)(15)(16)(17). Accordingly, xCT has been considered as a potential therapeutic target (13,14,16,17).…”

Section: Erastin Sensitizes Glioblastoma Cells To Temozolomide By Resmentioning

confidence: 99%

“…It is also associated with resistance to chemotherapy and poor survival (13)(14)(15)(16)(17). Accordingly, xCT has been considered as a potential therapeutic target (13,14,16,17). Sulfasalazine (SaSP) is a sulfa drug used for inflammatory bowel diseases and rheumatoid arthritis treatment and is a widely recognized xCT-specific inhibitor (18).…”

Section: Erastin Sensitizes Glioblastoma Cells To Temozolomide By Resmentioning

confidence: 99%

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Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function

et al. 2015

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Abstract. Glioblastoma multiforme (GBM) is one of the most common encephalic malignant tumors. Due to a high recurrence rate and a lack of effective treatments, the average survival rate remains low. Temozolomide (TMZ), a class of alkylating agent, is widely used as a first-line therapeutic drug during the adjuvant treatment for GBM patients. However, most patients exhibit a palpable resistance to TMZ treatment. Additionally, the underlying mechanism remains to be clarified. In this study, glutathione (GSH) and reactive oxygen species (ROS) levels were found to be closely associated with the sensitivity of GBM cells to TMZ. We also found that TMZ markedly induced xCT, the subunit of glutamate/cystine transporter system x c -expression, which together with the GSH synthesis was increased while the TMZ-inducible ROS level was decreased in GBM cells. In addition, the cystathionine γ-lyase (CTH) acivity, a key enzyme in the transsulfuration pathway was enhanced by TMZ, which insured a cysteine supply and GSH synthesis in a compensatory manner when xCT was blocked. Thus, the individual inhibition of xCT by siRNA and a pharmacological inhibitor (sulfasalazine) only partially inhibited GSH synthesis and moderately enhanced the GBM cell sensitivity to TMZ. However, the TMZ-induced cytotoxicity was markedly increased along with a marked decrease in GSH levels as result of co-treatment with erastin, which inhibited cysteine uptake from xCT transporter and suppressed CTH activity, leading to impaired transformation from methionine to cysteine. In conclusion, to GBM therapy with a drug combination of TMZ and erastin may be beneficial.

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Section: Erastin Sensitizes Glioblastoma Cells To Temozolomide By Resmentioning

confidence: 99%

Section: Erastin Sensitizes Glioblastoma Cells To Temozolomide By Resmentioning

confidence: 99%

Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function

et al. 2015

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“…xCT is essential for GSH synthesis and maintenance, which is a critical regulator of the cellular redox state (38). Thus, xCT has been considered as a potential target for cancer treatment, including tongue carcinoma (24). Previous studies have demonstrated that SASP enhances CDDP-inducible cytotoxicity by preventing electrophiles from conjugating with GSH, indicating that combined treatment with CDDP and SASP may be beneficial (31).…”

Section: Discussionmentioning

confidence: 99%

“…Notably, xCT is important in maintaining high levels of GSH and contributes to CDDP resistance of ovarian cancer cell lines (15). In addition, xCT is markedly upregulated in resected tongue carcinoma specimens (24). Ye et al (19) demonstrated that proteasome inhibitor-induced xCT expression is positively modulated by the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and activating transcription factor 4 (ATF4) via the antioxidant response element (ARE) and amino acid response element (AARE) on the promoter human xCT gene (19).…”

Section: Introductionmentioning

confidence: 99%

xCT expression modulates cisplatin resistance in Tca8113 tongue carcinoma cells

et al. 2016

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Abstract. Tongue squamous cell carcinoma (TSCC), which is a subtype of head and neck cancer, is the most common type of oral cancer. Due to its high recurrence rate and chemoresistance, the average survival rate for patients with TSCC remains unsatisfactory. At present, cisplatin (CDDP) is utilized as the first-line treatment for numerous solid neoplasms, including TSCC. CDDP resistance develops in the majority of patients; however, the mechanism of such resistance remains unknown. Therefore, the present study aimed to clarify the mechanism of CDDP resistance and attempted to reduce chemoresistance. The results indicated that CDDP significantly increased expression of xCT, which is the light chain and functional subunit of the glutamate/cysteine transporter system x c -, and a subsequent increase in glutathione (GSH) levels was observed. The present study demonstrated that the upregulation of xCT expression and intercellular GSH levels contributed to CDDP resistance in TSCC cells. Furthermore, xCT suppression, induced by small interfering RNA or pharmacological inhibitors, sensitized TSCC cells to CDDP treatment. In conclusion, the present study revealed that CDDP-induced xCT expression promotes CDDP chemoresistance, and xCT inhibition sensitizes TSCC cells to CDDP treatment. These results provide a novel insight into the molecular mechanisms involved in TSCC cell chemoresistance.

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“…previously demonstrated that HER2-type breast cancer expresses the highest SLC1A5 levels evaluated to date using immunohistochemistry. SLC1A5 expression is also associated with non-small cell lung cancer [10], lacrimal gland adenoid cystic carcinoma [11], oral squamous cell carcinoma [12], pancreatic ductal carcinoma [13], tongue cancer [14], and colorectal cancer [15]. Notably, while recent research has shown that SLC1A5 expression is increased in esophageal carcinoma [16], the biological significance of SLC1A5 in the development and/or progression of esophageal cancer has not been reported.…”

Section: Introductionmentioning

confidence: 99%

SLC1A5 Silencing Inhibits Esophageal Cancer Growth via Cell Cycle Arrest and Apoptosis

Lin¹,

Teng²,

Zheng³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Solute-linked carrier family A1 member 5 (SLC1A5), which has high affinity to neutral amino acids, is essential for glutamine transport and amino acid metabolism in various cancers. However, the role of SLC1A5 in esophageal cancer has not been reported. Methods: SLC1A5 expression in esophageal cancer tissues was detected by immunohistochemistry and western blotting. The effects of SLC1A5 knockdown on the growth, cell cycle, viability, and glutamine metabolism of esophageal cancer cells were investigated with flow cytometry and western blotting. Furthermore, the consequences of SLC1A5 knockdown on tumor growth and survival were also evaluated in vivo using mice carrying esophageal cancer xenografts. Results: SLC1A5 was expressed in 86.5% (32/37) of the cancer tissues from esophageal cancer patients. Moreover, SLC1A5 expression in the cancerous tissues was significantly higher than that in the paired adjacent normal tissues. SLC1A5 knockdown with siRNA (PZ siRNA) in TE-1 cells in vitro significantly decreased cell growth and reduced both leucine and glutamine transport, leading to inhibition of mTORC1 signaling. Additionally, siRNA-mediated SLC1A5 knockdown resulted in cell cycle arrest and apoptosis of TE-1 cells. The survival rate of athymic (nu/nu) male nude mice carrying tumors formed from TE-1 cells transfected with SLC1A5 siRNA (PZ siRNA) was also significantly improved compared with mice carrying tumors formed from TE-1 cells transfected with control siRNA. Tumor size/weight was also significantly lower for the former mice group of mice. Conclusion: Our data indicate that SLC1A5 plays an important role in esophageal cancer both in vivo and in vitro. The inhibition of esophageal cancer growth by targeting SLC1A5 could, therefore, be used as a preoperative therapy for esophageal cancer.

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Prognostic significance of amino-acid transporter expression (LAT1, ASCT2, and xCT) in surgically resected tongue cancer

Cited by 110 publications

References 27 publications

Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function

Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function

xCT expression modulates cisplatin resistance in Tca8113 tongue carcinoma cells

SLC1A5 Silencing Inhibits Esophageal Cancer Growth via Cell Cycle Arrest and Apoptosis

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