Targeting Amino Acid Transport in Metastatic Castration-Resistant Prostate Cancer: Effects on Cell Cycle, Cell Growth, and Tumor Development

Wang, Qian; Tiffen, Jessamy; Bailey, Charles G.; Lehman, Melanie; Ritchie, William; Fazli, Ladan; Metierre, Cynthia; Feng, Yulin; Li, Estelle; Gleave, Martin; Buchanan, Grant; Nelson, Colleen C.; Rasko, John E.J.; Holst, Jeff

doi:10.1093/jnci/djt241

Cited by 158 publications

(183 citation statements)

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“…The knockdown of human LAT1 by small interfering RNAs or stable transduction with lentivirus can also lead to the inhibition of cancer cell growth and migration (27). Similarly, down-regulating LAT1 can lead to decreased growth of prostate cancer cells (28) and human oral cancer cells (29). However, the over-expression of LAT1 has been suggested as a target for combination therapy with anti-proliferative aminopeptidase inhibitors to combat ovarian cancer (30).…”

Section: Clinical Significance Of Lat1 In Tumorsmentioning

confidence: 99%

The role of L-type amino acid transporter 1 in human tumors

Zhao

Wang

Pan

2015

IRDR

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Section: Clinical Significance Of Lat1 In Tumorsmentioning

confidence: 99%

The role of L-type amino acid transporter 1 in human tumors

Zhao

Wang

Pan

2015

IRDR

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“…It has been reported previously that the overexpression of SLC7 could contribute to the cellular growth and extension of cell cycles and thus, increase susceptibility to cancer (Wang et al, 2013). Thus far, only one study has reported the relationship between SLC7A7 polymorphisms and the development of glioma (Fan et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Association of three common single nucleotide polymorphisms of SLC7A7 with the development of glioma in a Chinese population

Zhang¹,

Shi²

2017

Genet. Mol. Res.

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ABSTRACT. Gliomas are brain tumors that can be seriously damaging to human health. The SLC7 family is involved in amino acid or peptide transportation. The relationship between SLC7A7 polymorphisms and the development of glioma has been reported previously by a few studies. Therefore, we performed a hospital based case-control study to investigate the association of three common SNPs (rs12888930, rs12436190, and rs2065134) of SLC7A7 with the development of glioma in a Chinese population. From January 2014 to December 2015, 122 patients with glioma and 252 individuals (controls) were recruited from the department of neurosurgery of Tangshan People's Hospital affiliated to North China University of Science and Technology. SLC7A7 rs12888930, rs12436190, and rs2065134 genotyping was performed by the polymerase chain reaction-restriction fragment length polymorphism method. Multiple logistic regression analysis showed that a significantly higher risk of glioma was harbored by the GG and AG + GG genotypes than by the AA genotype; OR (95%CI) was 2.24 (1.18-4.22) and 1.59 (1.01-2.60), respectively. However, no significant relationship was observed between SLC7A7 rs12888930 and rs2065134 and the risk of glioma. In conclusion, this study reports a significant association between SLC7A7 rs12436190 and the risk of glioma in a Chinese population.

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“…Imaging alternative metabolic pathways, including essential amino acid upregulation, has demonstrated clinical utility for several amino acid analogs [1,2]. survival [3][4][5]. Essential branched chain amino acids have shown a direct influence on critical growth and survival pathways through several mechanisms.…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, the essential amino acid L-leucine can directly stimulate the growth and survival of a tumor through activation of the critical mTORC1 pathway [3,5]. Inhibiting essential amino acid uptake through targeting amino acid transporters, thereby inhibiting leucine uptake, may offer a new therapeutic opportunity for the treatment of cancers by diminishing tumor growth and metastasis through inhibition of M-phase cell cycle and mTORC1 signaling pathways [4]. Several studies have shown that aggressive, therapy resistant cancers with worse prognosis are associated with overexpression of amino acid transporters such as LAT1 [6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Preliminary Evaluation of 5-[18F]fluoroleucine

Chin

McDougald

Weitzel

et al. 2017

CRP

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Background: Amino acid transporters, such as LAT1, are overexpressed in aggressive prostate and breast carcinomas, directly influencing pathways of growth and proliferation.Objective: The purpose of this study was to synthesize and characterize a novel 18 F labeled leucine analog, 5-[18 F]fluoroleucine, as a potential imaging agent for aggressive tumors which may not be amenable to imaging by FDG PET.Methods: 5-fluoroleucine was synthesized and characterized, and its 18 F-labeled analog was synthesized from a mesylate precursor. First, breast cancer cell line assays were performed to evaluate uptake of 3 H-or 14 C-labeled L-leucine and other essential amino acids. Both L-leucine and 5-[ 18 F]fluoroleucine were tested for uptake and accumulation over time, and for uptake via LAT1. Biodistribution studies were performed to estimate radiation dosimetry for human studies. Small animal PET / CT studies of a breast cancer were performed to evaluate in vivo 5-[18 F]fluoroleucine tumor uptake. Results: Breast cancer cell lines showed increasing high net accumulation of L-[14 C]leucine. Both L-leucine and 5-[18 F]fluoroleucine showed increasing uptake over time in in vitro tumor cell assays, and uptake was also shown to occur via LAT1. The biodistribution study of 5-[18 F]fluoroleucine showed rapid renal excretion, no significant in vivo metabolism, and acceptable dosimetry for use in humans. In vivo small animal PET / CT imaging of a breast cancer xenograft showed uptake of 5-[ 18 F]fluoroleucine in the tumor, which progressively increased over time. Conclusion: 5-[18 F]fluoroleucine is a leucine analog which may be useful in identifying tumors with high or upregulated expression of amino acid transporters, providing additional information that may not be provided by FDG PET.

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Targeting Amino Acid Transport in Metastatic Castration-Resistant Prostate Cancer: Effects on Cell Cycle, Cell Growth, and Tumor Development

Abstract: Inhibition of LAT transporters may provide a novel therapeutic target in metastatic castration-resistant prostate cancer, via suppression of mammalian target of rapamycin complex 1 activity and M-phase cell cycle genes.

Cited by 158 publications

References 50 publications

The role of L-type amino acid transporter 1 in human tumors

The role of L-type amino acid transporter 1 in human tumors

Association of three common single nucleotide polymorphisms of SLC7A7 with the development of glioma in a Chinese population

Synthesis and Preliminary Evaluation of 5-[18F]fluoroleucine

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