Glutamine promotes ovarian cancer cell proliferation through the mTOR/S6 pathway

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Glutamine is one of the main nutrients used by tumor cells for biosynthesis. Therefore, targeted inhibition of glutamine metabolism may have anti-tumorigenic implications. In the present study, we aimed to evaluate the effects of glutamine on ovarian cancer cell growth. Three ovarian cancer cell lines, HEY, SKOV3, and IGROV-1, were assayed for glutamine dependence by analyzing cytotoxicity, cell cycle progression, apoptosis, cell stress, and glucose/glutamine metabolism. Our results revealed that administration of glutamine increased cell proliferation in all three ovarian cancer cell lines in a dose dependent manner. Depletion of glutamine induced reactive oxygen species and expression of endoplasmic reticulum stress proteins. In addition, glutamine increased the activity of glutaminase (GLS) and glutamate dehydrogenase (GDH) by modulating the mTOR/S6 and MAPK pathways. Inhibition of mTOR activity by rapamycin or blocking S6 expression by siRNA inhibited GDH and GLS activity, leading to a decrease in glutamine-induced cell proliferation. These studies suggest that targeting glutamine metabolism may be a promising therapeutic strategy in the treatment of ovarian cancer.

Related collections

Most cited references 51

Record: found
Abstract: found
Article: not found

Bidirectional transport of amino acids regulates mTOR and autophagy.

Paul Nicklin, Philip Bergman, Bailin Zhang … (2009)

Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase which regulates protein translation, cell growth, and autophagy. Cell surface transporters that allow amino acids to enter the cell and signal to mTOR are unknown. We show that cellular uptake of L-glutamine and its subsequent rapid efflux in the presence of essential amino acids (EAA) is the rate-limiting step that activates mTOR. L-glutamine uptake is regulated by SLC1A5 and loss of SLC1A5 function inhibits cell growth and activates autophagy. The molecular basis for L-glutamine sensitivity is due to SLC7A5/SLC3A2, a bidirectional transporter that regulates the simultaneous efflux of L-glutamine out of cells and transport of L-leucine/EAA into cells. Certain tumor cell lines with high basal cellular levels of L-glutamine bypass the need for L-glutamine uptake and are primed for mTOR activation. Thus, L-glutamine flux regulates mTOR, translation and autophagy to coordinate cell growth and proliferation.

0 comments Cited 638 times – based on 0 reviews      Review now

Record: found
Abstract: found
Article: found

Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer.

Matt I Gross, Susan D Demo, Jennifer B. Dennison … (2014)

Glutamine serves as an important source of energy and building blocks for many tumor cells. The first step in glutamine utilization is its conversion to glutamate by the mitochondrial enzyme glutaminase. CB-839 is a potent, selective, and orally bioavailable inhibitor of both splice variants of glutaminase (KGA and GAC). CB-839 had antiproliferative activity in a triple-negative breast cancer (TNBC) cell line, HCC-1806, that was associated with a marked decrease in glutamine consumption, glutamate production, oxygen consumption, and the steady-state levels of glutathione and several tricarboxylic acid cycle intermediates. In contrast, no antiproliferative activity was observed in an estrogen receptor-positive cell line, T47D, and only modest effects on glutamine consumption and downstream metabolites were observed. Across a panel of breast cancer cell lines, GAC protein expression and glutaminase activity were elevated in the majority of TNBC cell lines relative to receptor positive cells. Furthermore, the TNBC subtype displayed the greatest sensitivity to CB-839 treatment and this sensitivity was correlated with (i) dependence on extracellular glutamine for growth, (ii) intracellular glutamate and glutamine levels, and (iii) GAC (but not KGA) expression, a potential biomarker for sensitivity. CB-839 displayed significant antitumor activity in two xenograft models: as a single agent in a patient-derived TNBC model and in a basal like HER2(+) cell line model, JIMT-1, both as a single agent and in combination with paclitaxel. Together, these data provide a strong rationale for the clinical investigation of CB-839 as a targeted therapeutic in patients with TNBC and other glutamine-dependent tumors.

0 comments Cited 447 times – based on 0 reviews      Review now

Record: found
Abstract: found
Article: not found

Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function.

W. Hu, C. Zhang, R. Wu … (2010)

Whereas cell cycle arrest, apoptosis, and senescence are traditionally thought of as the major functions of the tumor suppressor p53, recent studies revealed two unique functions for this protein: p53 regulates cellular energy metabolism and antioxidant defense mechanisms. Here, we identify glutaminase 2 (GLS2) as a previously uncharacterized p53 target gene to mediate these two functions of the p53 protein. GLS2 encodes a mitochondrial glutaminase catalyzing the hydrolysis of glutamine to glutamate. p53 increases the GLS2 expression under both nonstressed and stressed conditions. GLS2 regulates cellular energy metabolism by increasing production of glutamate and alpha-ketoglutarate, which in turn results in enhanced mitochondrial respiration and ATP generation. Furthermore, GLS2 regulates antioxidant defense function in cells by increasing reduced glutathione (GSH) levels and decreasing ROS levels, which in turn protects cells from oxidative stress (e.g., H(2)O(2))-induced apoptosis. Consistent with these functions of GLS2, the activation of p53 increases the levels of glutamate and alpha-ketoglutarate, mitochondrial respiration rate, and GSH levels and decreases reactive oxygen species (ROS) levels in cells. Furthermore, GLS2 expression is lost or greatly decreased in hepatocellular carcinomas and the overexpression of GLS2 greatly reduced tumor cell colony formation. These results demonstrated that as a unique p53 target gene, GLS2 is a mediator of p53's role in energy metabolism and antioxidant defense, which can contribute to its role in tumor suppression.

0 comments Cited 360 times – based on 0 reviews      Review now

All references

Author and article information

Journal

Journal ID (nlm-ta): Endocr Relat Cancer

Journal ID (iso-abbrev): Endocr. Relat. Cancer

Journal ID (publisher-id): ERC

Title: Endocrine-Related Cancer

Publisher: Bioscientifica Ltd (Bristol )

ISSN (Print): 1351-0088

ISSN (Electronic): 1479-6821

Publication date (Print): August 2015

Publication date (Electronic preprint): 4 June 2015

Volume: 22

Issue: 4

Pages: 577-591

Affiliations

[1]Department of Gynecologic Oncology , ShanDong Tumor Hospital and Cancer Institute, Jinan University , Jinan, 250117, People's Republic of China

[2]Division of Gynecologic Oncology , University of North Carolina at Chapel Hill , CB #7572, Physicians Office Building Rm #B105, Chapel Hill, North Carolina, 27599, USA

[3]Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina, USA

Author notes

Correspondence should be addressed to V L Bae-Jump or C Zhou Emsils; victoria_baejump@ 123456med.unc.edu or czhou@ 123456med.unc.edu

Article

Publisher ID: ERC150192

DOI: 10.1530/ERC-15-0192

PMC ID: 4500469

PubMed ID: 26045471

SO-VID: 00383380-401e-4c6d-8e4b-ed63c9065ff1

License:

This work is licensed under a Creative Commons Attribution 3.0 Unported License

History

Date revision received : 28 May 2015

Date accepted : 4 June 2015

Comments

Comment on this article

Cited by 52

See all cited by

Most referenced authors 1,249

See all reference authors

The flagship journal of the Society for Endocrinology. Learn more