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Amino Acid Transporters and Signaling in Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 17781

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Special Issue Editors

Dr. Barrie P. Bode

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Guest Editor

Department of Biological Sciences, Northern Illinois University, DeKalb, IL 60115, USA
Interests: amino acid transporters; cancer; glutamine metabolism

Dr. Neetika Khurana

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Guest Editor

Department of Biological Sciences, Northern Illinois University, DeKalb, IL 60115, USA

Special Issue Information

Dear Colleagues,

Metabolic reprogramming in cancer is recognized as a common and integral component of multistep tumorigenesis. Among nutrients, amino acids are central to growth signaling and cellular stress responses; likewise, the cellular machinery involved in delivering and sustaining the amino acid ecosystem is often altered in the course of cancer metabolic reprogramming. As such, amino acid transporters, metabolic enzymes, and signaling proteins are actively investigated as potential targets for cancer therapies. This Special Issue of the International Journal of Molecular Sciences focuses on the role of amino acid transporters and linked signaling proteins involved in cell-autonomous cancer growth and tumorigenesis. Papers are sought particularly in the area of transporter targeting and its effects on metabolism, growth, and stress response signaling in cancer cells and the tumors that they spawn. This rapidly emerging area of research is poised to be an integral component of advances in cancer therapy either directly, or as an adjuvant, as we move into the 2020s.

Dr. Barrie P. Bode
Dr. Neetika Khurana
Guest Editors

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Keywords

Amino acid transporter
Cancer
Integrated stress response
Glutathione
mTOR
Tumorigenesis
Glutamine
Metabolism
Oxidative stress
Cell growth

Published Papers (4 papers)

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Research

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12 pages, 955 KiB

Open AccessArticle

Overexpression of miR-375 and L-type Amino Acid Transporter 1 in Pheochromocytoma and Their Molecular and Functional Implications

by Jacopo Manso, Loris Bertazza, Susi Barollo, Alberto Mondin, Simona Censi, Sofia Carducci, Alfonso Massimiliano Ferrara, Isabella Merante Boschin, Stefania Zovato, Francesca Schiavi, Michele Gregianin, Gianmaria Pennelli, Maurizio Iacobone and Caterina Mian

Int. J. Mol. Sci. 2022, 23(5), 2413; https://doi.org/10.3390/ijms23052413 - 22 Feb 2022

Cited by 5 | Viewed by 1834

Abstract

Pheochromocytoma (Pheo) is a tumor derived from chromaffin cells. It can be studied using 18F-dihydroxyphenylalanine (DOPA)—positron emission tomography (PET) due to its overexpression of L-type amino acid transporters (LAT1 and LAT2). The oncogenic pathways involved are still poorly understood. This study examined the relationship between ¹⁸F-DOPA-PET uptake and LAT1 expression, and we explored the role of miR-375 and putative target genes. A consecutive series of 58 Pheo patients were retrospectively analyzed, performing ¹⁸F-DOPA-PET in 32/58 patients. Real-time quantitative PCR was used to assess the expression of LAT1, LAT2, phenylethanolamine N-methyltransferase (PNMT), miR-375, and the major components of the Hippo and Wingless/Integrated pathways. Principal germline mutations associated with hereditary Pheo were also studied. Pheo tissues had significantly higher LAT1, LAT2, and PNMT mRNA levels than normal adrenal tissues. MiR-375 was strongly overexpressed. Yes-associated protein 1 and tankyrase 1 were upregulated, while beta-catenin, axin2, monocarboxylate transporter 8, and Frizzled 8 were downregulated. A positive relationship was found between ¹⁸F-DOPA-PET SUV mean and LAT1 gene expression and for 24 h-urinary norepinephrine and LAT1. This is the first experimental evidence of ¹⁸F-DOPA uptake correlating with LAT1 overexpression. We also demonstrated miR-375 overexpression and downregulated (Wnt) signaling and identified the Hippo pathway as a new potentially oncogenic feature of Pheo. Full article

(This article belongs to the Special Issue Amino Acid Transporters and Signaling in Cancer)

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15 pages, 1911 KiB

Open AccessArticle

Tyrosine–Chlorambucil Conjugates Facilitate Cellular Uptake through L-Type Amino Acid Transporter 1 (LAT1) in Human Breast Cancer Cell Line MCF-7

by Piman Pocasap, Natthida Weerapreeyakul, Juri Timonen, Juulia Järvinen, Jukka Leppänen, Jussi Kärkkäinen and Jarkko Rautio

Int. J. Mol. Sci. 2020, 21(6), 2132; https://doi.org/10.3390/ijms21062132 - 20 Mar 2020

Cited by 10 | Viewed by 3664

Abstract

l-type amino acid transporter 1 (LAT1) is an amino acid transporter that is overexpressed in several types of cancer and, thus, it can be a potential target for chemotherapy. The objectives of this study were to (a) synthesize LAT1-targeted chlorambucil derivatives and (b) evaluate their LAT1-mediated cellular uptake as well as antiproliferative activity in vitro in the human breast cancer MCF-7 cell line. Chlorambucil was conjugated to l-tyrosine—an endogenous LAT1 substrate—via either ester or amide linkage (compounds 1 and 2, respectively). While chlorambucil itself did not bind to LAT1, its derivatives 1 and 2 bound to LAT1 with a similar affinity as with l-tyrosine and their respective cellular uptake was significantly higher than that of chlorambucil in MCF-7. The results of our cellular uptake study are indicative of antiproliferative activity, as a higher intracellular uptake of chlorambucil derivatives resulted in greater cytotoxicity than chlorambucil by itself. LAT1 thus contributes to intracellular uptake of chlorambucil derivatives and, therefore, increases antiproliferative activity. The understanding gained from our research can be used in the development of LAT1-targeted anticancer drugs and prodrugs for site-selective and enhanced chemotherapeutic activity. Full article

(This article belongs to the Special Issue Amino Acid Transporters and Signaling in Cancer)

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20 pages, 1473 KiB

Open AccessReview

Amino Acid Transporters Are a Vital Focal Point in the Control of mTORC1 Signaling and Cancer

by Yann Cormerais, Milica Vučetić, Scott K. Parks and Jacques Pouyssegur

Int. J. Mol. Sci. 2021, 22(1), 23; https://doi.org/10.3390/ijms22010023 - 22 Dec 2020

Cited by 20 | Viewed by 4935

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) integrates signals from growth factors and nutrients to control biosynthetic processes, including protein, lipid, and nucleic acid synthesis. Dysregulation in the mTORC1 network underlies a wide array of pathological states, including metabolic diseases, neurological disorders, and cancer. Tumor cells are characterized by uncontrolled growth and proliferation due to a reduced dependency on exogenous growth factors. The genetic events underlying this property, such as mutations in the PI3K-Akt and Ras-Erk signaling networks, lead to constitutive activation of mTORC1 in nearly all human cancer lineages. Aberrant activation of mTORC1 has been shown to play a key role for both anabolic tumor growth and resistance to targeted therapeutics. While displaying a growth factor-independent mTORC1 activity and proliferation, tumors cells remain dependent on exogenous nutrients such as amino acids (AAs). AAs are an essential class of nutrients that are obligatory for the survival of any cell. Known as the building blocks of proteins, AAs also act as essential metabolites for numerous biosynthetic processes such as fatty acids, membrane lipids and nucleotides synthesis, as well as for maintaining redox homeostasis. In most tumor types, mTORC1 activity is particularly sensitive to intracellular AA levels. This dependency, therefore, creates a targetable vulnerability point as cancer cells become dependent on AA transporters to sustain their homeostasis. The following review will discuss the role of AA transporters for mTORC1 signaling in cancer cells and their potential as therapeutic drug targets. Full article

(This article belongs to the Special Issue Amino Acid Transporters and Signaling in Cancer)

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20 pages, 1427 KiB

Open AccessReview

Amino Acid Transporters as Targets for Cancer Therapy: Why, Where, When, and How

by Stefan Bröer

Int. J. Mol. Sci. 2020, 21(17), 6156; https://doi.org/10.3390/ijms21176156 - 26 Aug 2020

Cited by 60 | Viewed by 6743

Abstract

Amino acids are indispensable for the growth of cancer cells. This includes essential amino acids, the carbon skeleton of which cannot be synthesized, and conditionally essential amino acids, for which the metabolic demands exceed the capacity to synthesize them. Moreover, amino acids are important signaling molecules regulating metabolic pathways, protein translation, autophagy, defense against reactive oxygen species, and many other functions. Blocking uptake of amino acids into cancer cells is therefore a viable strategy to reduce growth. A number of studies have used genome-wide silencing or knock-out approaches, which cover all known amino acid transporters in a large variety of cancer cell lines. In this review, these studies are interrogated together with other databases to identify vulnerabilities with regard to amino acid transport. Several themes emerge, such as synthetic lethality, reduced redundancy, and selective vulnerability, which can be exploited to stop cancer cell growth. Full article

(This article belongs to the Special Issue Amino Acid Transporters and Signaling in Cancer)

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