JPH203, a selective L-type amino acid transporter 1 inhibitor, induces mitochondria-dependent apoptosis in Saos2 human osteosarcoma cells

Choi, Dae Woo; Kim, Do Kyung; Kanai, Yoshikatsu; Wempe, Michael F.; Endou, Hitoshi; Kim, Jong Keun

doi:10.4196/kjpp.2017.21.6.599

Cited by 29 publications

(25 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of them, several reports have provided the molecular analysis and showed the anti-tumor proliferation mechanism by western blot assay, through downregulating the phosphorylation of mTOR pathway proteins such as p70S6K, and S6, and upregulating the phosphorylation of 4EBP1 31–33 . Moreover, JPH203 activated the mitochondria-dependent apoptotic signaling pathway by upregulating pro-apoptotic factors, such as Bad, Bax, and Bak, and the active form of caspase-9, and downregulating anti-apoptotic factors, such as Bcl-2 and Bcl-xL in human osteosarcoma Saos2 cells 35 . The other groups also showed induction of the apoptosis in oral cancer YD-38 cells 36 .…”

Section: Discussionmentioning

confidence: 98%

A novel therapeutic approach for anaplastic thyroid cancer through inhibition of LAT1

Enomoto

Sato

Tamagawa

et al. 2019

Sci Rep

View full text Add to dashboard Cite

A novel therapeutic approach is urgently needed for patients with anaplastic thyroid cancer (ATC) due to its fatal and rapid progress. We recently reported that ATC highly expressed MYC protein and blocking of MYC through its selective inhibitor, JQ1, decreased ATC growth and improved survival in preclinical models. One of the important roles of MYC is regulation of L-neutral amino acid transporter 1 (LAT1) protein and inhibition of LAT1 would provide similar anti-tumor effect. We first identified that while the human ATC expresses LAT1 protein, it is little or not detected in non-cancerous thyroidal tissue, further supporting LAT1 as a good target. Then we evaluated the efficacy of JPH203, a LAT1 inhibitor, against ATC by using the in vitro cell-based studies and in vivo xenograft model bearing human ATC cells. JPH203 markedly inhibited proliferation of three ATC cell lines through suppression of mTOR signals and blocked cell cycle progression from the G0/G1 phase to the S phase. The tumor growth inhibition and decrease in size by JPH203 via inhibition of mTOR signaling and G0/G1 cell cycle associated proteins were further confirmed in xenograft models. These preclinical findings suggest that LAT1 inhibitors are strong candidates to control ATC, for which current treatment options are highly limited.

show abstract

Section: Discussionmentioning

confidence: 98%

A novel therapeutic approach for anaplastic thyroid cancer through inhibition of LAT1

Enomoto

Sato

Tamagawa

et al. 2019

Sci Rep

View full text Add to dashboard Cite

show abstract

“…In previous studies, the selective inhibition of LAT1 by JPH203 has been demonstrated. Several groups reported that JPH203 inhibits the proliferation of cancer cells by inhibiting L-leucine uptake 13,18,26 , LAT1 has been shown to affect cancer cell proliferation through the mTOR signalling pathway in pancreatic cancer 27 , lung cancer 28 , and prostate cancer 6,29 . Leucine is an essential amino acid that must be taken from outside the cells and activates mTOR signals.…”

Section: Discussionmentioning

confidence: 99%

Expression of L-type amino acid transporter 1 as a molecular target for prognostic and therapeutic indicators in bladder carcinoma

Maimaiti

Sakamoto

Yamada

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

L-type amino acid transporter 1 (LAT1) plays a role in transporting essential amino acids including leucine, which regulates the mTOR signaling pathway. Here, we studied the expression profile and functional role of LAT1 in bladder cancer. Furthermore, the pharmacological activity of JPH203, a specific inhibitor of LAT1, was studied in bladder cancer. LAT1 expression in bladder cancer cells was higher than that in normal cells. SiLAT1 and JPH203 suppressed cell proliferative and migratory and invasive abilities in bladder cancer cells. JPH203 inhibited leucine uptake by > 90%. RNA-seq analysis identified insulin-like growth factor-binding protein-5 (IGFBP-5) as a downstream target of JPH203. JPH203 inhibited phosphorylation of MAPK / Erk, AKT, p70S6K and 4EBP-1. Multivariate analysis revealed that high LAT1 expression was found as an independent prognostic factor for overall survival (HR3.46 P = 0.0204). Patients with high LAT1 and IGFBP-5 expression had significantly shorter overall survival periods than those with low expression (P = 0.0005). High LAT1 was related to the high Grade, pathological T stage, LDH, and NLR. Collectively, LAT1 significantly contributed to bladder cancer progression. Targeting LAT1 by JPH203 may represent a novel therapeutic option in bladder cancer treatment.Bladder cancer (BC) is the ninth most common malignant tumour worldwide, with 430 000 patients newly diagnosed and 165 000 deaths annually 1 . The pathological type of BC is mainly urothelial cancer ( > 90%) and approximately 70% of patients had non-muscle-invasive BC at diagnosis 2 . These patients have a favorable prognosis with transurethral resection and subsequent intravesical injection therapy, whereas the survival rate of patients with locally advanced and metastatic BC is poor 3 . For metastatic BC patients, platinum-based systematic chemotherapy is the classical treatment, while immunotherapy targeting programmed cell death ligand 1 (PD-L1) blocking antibody was recently approved in Japan 4 . However, drug resistance will occur, and the survival benefit of these agents is not adequate. Their limited efficacy is due to side effects and challenges of drug resistance, leading to treatment failure and require additional treatment options 5 . Therefore, more effective and less toxic therapeutic strategies are needed for the treatment of metastatic BC. Additionally, there are presently no useful diagnostic markers for BC. The urine cytology test is a non-invasive examination, but its sensitivity remains low. Cystoscopy is an essential diagnostic tool but is invasive for patients 5 . Thus, a novel therapeutic approach and biomarker candidates for BC remain a major issue.

show abstract

“…It is worth to note that the tyrosine analog JPH203, previously known as KYT-0353, is a potent inhibitor (Oda et al, 2010 ) both in vitro and in mouse model of HT-29 tumors (colon cancer) (Oda et al, 2010 ; Wempe et al, 2012 ; Toyoshima et al, 2013 ). The molecular mechanism of action of JPH203, investigated using osteosarcoma cell line (Choi et al, 2017 ), consists in activating the mitochondrial pro-apoptotic pathway. This inhibitor is effective also in different type of cancers (Rosilio et al, 2015 ; Hayashi et al, 2016 ; Choi et al, 2017 ; Otsuki et al, 2017 ; Yothaisong et al, 2017 ).…”

Section: Lat1 Druggability and Clinical Outcomesmentioning

confidence: 99%

“…The molecular mechanism of action of JPH203, investigated using osteosarcoma cell line (Choi et al, 2017 ), consists in activating the mitochondrial pro-apoptotic pathway. This inhibitor is effective also in different type of cancers (Rosilio et al, 2015 ; Hayashi et al, 2016 ; Choi et al, 2017 ; Otsuki et al, 2017 ; Yothaisong et al, 2017 ). Moreover, a synergistic effect with metformin is observed in a cell line of HNC (Head and Neck Cancer) in vitro and in mouse-transplanted model (Ueno et al, 2016 ).…”

Section: Lat1 Druggability and Clinical Outcomesmentioning

confidence: 99%

The Human SLC7A5 (LAT1): The Intriguing Histidine/Large Neutral Amino Acid Transporter and Its Relevance to Human Health

et al. 2018

View full text Add to dashboard Cite

SLC7A5, known as LAT1, belongs to the APC superfamily and forms a heterodimeric amino acid transporter interacting with the glycoprotein CD98 (SLC3A2) through a conserved disulfide. The complex is responsible for uptake of essential amino acids in crucial body districts such as placenta and blood brain barrier. LAT1/CD98 heterodimer has been studied over the years to unravel the transport mechanism and the role of each subunit. Studies conducted in intact cells demonstrated that LAT1/CD98 mediates a Na+ and pH independent antiport of amino acids. Some novel insights into the function of LAT1 derived from studies conducted in proteoliposomes reconstituted with the recombinant human LAT1. Using this experimental tool, it has been demonstrated that the preferred substrate is histidine and that CD98 is not required for transport being, plausibly, involved in routing LAT1 to the plasma membrane. Since a 3D structure of LAT1 is not available, homology models have been built on the basis of the AdiC transporter from E.coli. Crucial residues for substrate recognition and gating have been identified using a combined approach of bioinformatics and site-directed mutagenesis coupled to functional assays. Over the years, the interest around LAT1 increased because this transporter is involved in important human diseases such as neurological disorders and cancer. Therefore, LAT1 became an important pharmacological target together with other nutrient membrane transporters. Moving from knowledge on structure/function relationships, two cysteine residues, lying on the substrate binding site, have been exploited for designing thiol reacting covalent inhibitors. Some lead compounds have been characterized whose efficacy has been tested in a cancer cell line.

show abstract

JPH203, a selective L-type amino acid transporter 1 inhibitor, induces mitochondria-dependent apoptosis in Saos2 human osteosarcoma cells

Cited by 29 publications

References 28 publications

A novel therapeutic approach for anaplastic thyroid cancer through inhibition of LAT1

A novel therapeutic approach for anaplastic thyroid cancer through inhibition of LAT1

Expression of L-type amino acid transporter 1 as a molecular target for prognostic and therapeutic indicators in bladder carcinoma

The Human SLC7A5 (LAT1): The Intriguing Histidine/Large Neutral Amino Acid Transporter and Its Relevance to Human Health

Contact Info

Product

Resources

About