Prostate Cancer Cells in Different Androgen Receptor Status Employ Different Leucine Transporters

Otsuki, Hideo; Kimura, Tōru; Yamaga, Takashi; Kosaka, Takeo; Suehiro, Jun Ichi; Sakurai, Hiroyuki

doi:10.1002/pros.23263

Cited by 34 publications

(24 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…22,23 Inhibiting leucine transporters could lead to significant cell growth inhibition in PCa cells as well as tumor growth and metastasis in xenografts, suggesting anti-leucine transporter therapy could be employed as an important option against PCa. 23,24 Our study found high expression of MCCC2 in highly proliferative PCa cell line 22RV1 whereas low expression in low-speed proliferative cell line LNCaP, the difference in MCCC2 expression reflects energy supply which is important for cancer cell proliferation. We also confirmed MCCC2 associated with unfavorable clinical features and promoted aggressiveness of PCa cells in vitro, adding evidence that MCCC2 may modulate leucine metabolism to exhibit an oncogenic role in PCa.…”

Section: Discussionmentioning

confidence: 67%

<p>Methylcrotonoyl-CoA Carboxylase 2 Promotes Proliferation, Migration and Invasion and Inhibits Apoptosis of Prostate Cancer Cells Through Regulating GLUD1-P38 MAPK Signaling Pathway</p>

Jian-xin

Mao

Huang

et al. 2020

OTT

View full text Add to dashboard Cite

Prostate cancer (PCa) is the most common cancer in American men, and the mechanisms of development and progression are still not completely clear. Methylcrotonoyl-CoA carboxylase 2 (MCCC2) was previously identified overexpressed in PCa with lymph node metastasis, but its specific role and mechanisms need further investigation. This study aimed to investigate the role of MCCC2 in PCa cells and its underlying mechanisms. Materials and Methods: Quantitative RT-PCR and Western blotting were used to detect MCCC2 mRNA and protein expression in normal prostate epithelium and cancerous cells. Upon manipulation of MCCC2 expression, cell proliferation was measured by CCK-8 assays and migration and invasion were determined by transwell assays. Changes of apoptosis, cell cycle and mitochondrial membrane potential were evaluated by flow cytometry. MCCC2-mediated signaling pathways were screened by bioinformatics and verified by RT-PCR and Western blotting. Finally, immunohistochemistry was performed to detect the expression of MCCC2 and glutamate dehydrogenase 1 (GLUD1) in PCa tissues to analyze their correlation. Results: We demonstrated that MCCC2 promoted cell proliferation, migration and invasion but inhibited apoptosis in PCa cells. In addition, MCCC2 in 22Rv1 cells induced mitochondrial damage. In PCa tissues, MCCC2 overexpression associated with lymph node metastasis (P=0.001) and high Gleason scores (P<0.001). MCCC2 positively correlated with GLUD1 expression in PCa tissues (r=0.435, P<0.001). Ectopic overexpression of MCCC2 up-regulated GLUD1 and p38 MAPK expression, whereas inhibition of MCCC2 decreased GLUD1 and p38 MAPK expression. Conclusion: MCCC2 exerts oncogenic function in PCa through regulating GLUD1-p38 MAPK signaling pathway, and it may be a potential treatment target.

show abstract

Section: Discussionmentioning

confidence: 67%

<p>Methylcrotonoyl-CoA Carboxylase 2 Promotes Proliferation, Migration and Invasion and Inhibits Apoptosis of Prostate Cancer Cells Through Regulating GLUD1-P38 MAPK Signaling Pathway</p>

Jian-xin

Mao

Huang

et al. 2020

OTT

View full text Add to dashboard Cite

show abstract

“…Thus, JX009 is the first characterized System L‐specific leucine uptake inhibitor in the low µM‐range (EC 50 < 4 µmol/L; Figure 4) for use in placental cell models. To date, the most widely used SLC7‐specific inhibitor is the non‐metabolizable leucine analog BCH which has been also tested in this study (Figure 4D) and other investigations 51,52 . In comparison to JX009 this inhibitor is >100‐times less effective and blocks System L‐dependent AA transport with 709 µmol/L in BeWo‐CTB and 442 µmol/L in BeWo‐STB in the high µM‐range (Figure 4D).…”

Section: Discussionmentioning

confidence: 89%

Small molecule inhibitors provide insights into the relevance of LAT1 and LAT2 in materno‐foetal amino acid transport

Zaugg

Huang

Ziegler

et al. 2020

J Cellular Molecular Medi

View full text Add to dashboard Cite

Adequate amino acid (AA) supply is vital especially for highly proliferative tissues like the placenta. Other tissues which are critical for nutrient absorption and transport, such as the intestine and liver, mainly use the efficient sodium (Na +)-dependent uptake maintained by System A transporters, 1 such as the SNAT family. 2 The heteromeric SLC7 AA transporters, a subgroup of the System L-exchanger

show abstract

“…It has reported that JPH203 did not inhibit L-leucine uptake mediated by human LAT2 overexpressing cells ( 28 ). In addition, L-leucine uptake by LNCaP cells, a LAT3 and LAT4-domionant prostate cancer cell line, was not altered by treatment of JPH203, even though the uptake was significantly decreased by treatment of BCH ( 29 ), indicating that JPH203 has a high specificity for the inhibition of LAT1 among system L. We demonstrated the significant decreasing in the pregabalin uptake by hCMEC/D3 cells in either case of the treatment of JPH203 and LAT1 siRNA (Table III and Fig. 3b ).…”

Section: Discussionmentioning

confidence: 96%

Transport of Pregabalin Via L-Type Amino Acid Transporter 1 (SLC7A5) in Human Brain Capillary Endothelial Cell Line

et al. 2018

View full text Add to dashboard Cite

PurposeThe anti-epileptic drug pregabalin crosses the blood-brain barrier (BBB) in spite of its low lipophilicity. This study was performed to determine whether L-type amino acid transporters (LAT1/SLC7A5 and LAT2/SLC7A8) contribute to the uptake of pregabalin.MethodsPregabalin uptake by LATs-transfected HEK293 cells or hCMEC/D3 cells, an in vitro human BBB model, was measured by LC-MS/MS analysis. Expression of LAT1 mRNA in hCMEC/D3 cells was determined by quantitative RT-PCR analysis.ResultsOverexpression of LAT1, but not LAT2, in HEK293 cells significantly increased the cellular uptake of pregabalin, and the LAT1-mediated uptake was saturable with a Km of 0.288 mM. LAT1-mediated amino acid uptake was inhibited specifically and almost completely in the presence of 1 mM pregabalin. The uptake of pregabalin by hCMEC/D3 cells was sodium-independent, saturable (Km = 0.854 mM), and strongly inhibited by large amino acids at 1 mM, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid, a specific system L inhibitor, at 1 mM and by JPH203, a LAT1-selective inhibitor, at 10 μM. Pregabalin uptake in hCMEC/D3 cells was also decreased by 75% by the silencing of LAT1 gene using LAT1 siRNA.ConclusionsOur results indicate that LAT1, but not LAT2, recognizes pregabalin as a substrate. It is suggested that LAT1 mediates pregabalin transport at the BBB.Electronic supplementary materialThe online version of this article (10.1007/s11095-018-2532-0) contains supplementary material, which is available to authorized users.

show abstract

Prostate Cancer Cells in Different Androgen Receptor Status Employ Different Leucine Transporters

Abstract: New CRPC cell line with increased expression of y LAT2 as a leucine transporter was established in vitro. Anti-leucine transporter therapy could be an important option against prostate cancer. Prostate 77:222-233, 2017. © 2016 Wiley Periodicals, Inc.

Cited by 34 publications

References 34 publications

<p>Methylcrotonoyl-CoA Carboxylase 2 Promotes Proliferation, Migration and Invasion and Inhibits Apoptosis of Prostate Cancer Cells Through Regulating GLUD1-P38 MAPK Signaling Pathway</p>

<p>Methylcrotonoyl-CoA Carboxylase 2 Promotes Proliferation, Migration and Invasion and Inhibits Apoptosis of Prostate Cancer Cells Through Regulating GLUD1-P38 MAPK Signaling Pathway</p>

Small molecule inhibitors provide insights into the relevance of LAT1 and LAT2 in materno‐foetal amino acid transport

Transport of Pregabalin Via L-Type Amino Acid Transporter 1 (SLC7A5) in Human Brain Capillary Endothelial Cell Line

Contact Info

Product

Resources

About