title: Glutamine deprivation sensitizes human breast cancer MDA-MB-231 cells to TRIAL-mediated apoptosis.
abstract: Tumor cell metabolism is a promising target for various cancer treatments. Apart from aerobic glycolysis, cancer cell growth is dependent on glutamine (Gln) supply, leading to their survival and differentiation. Therefore, we examined whether treatment with TNF-related apoptosis-inducing ligand (TRAIL) sensitizes MDA-MB-231 cells to apoptosis under Gln deprivation condition (TRAIL/Gln deprivation). Gln deprivation decreased cell proliferation as expected, but did not induce remarkable cell death. TRAIL/Gln deprivation, however, significantly increased growth inhibition and morphological shrinkage of MDA-MB-231 cells compared to those induced by treatment with either Gln deprivation or TRAIL alone. Moreover, TRAIL/Gln deprivation upregulated the apoptotic sub-G1phase accompanied with a remarkable decrease of pro-caspase-3, pro-caspase-9, and anti-apoptotic xIAP, and Bcl-2. Increased cleavage of PARP and pro-apoptotic Bid protein expression suggests that TRAIL/Gln deprivation triggers mitochondrion-mediated apoptosis in MDA-MB-231 cells. Additionally, TRAIL/Gln deprivation upregulated the expression of endoplasmic reticulum (ER) stress markers such as ATF4 and phosphorylated eIF2α, thereby enhancing the C/EBP homologous protein (CHOP) protein level. Transient knockdown of CHOP partically reversed TRAIL/Gln deprivation-mediated apoptosis. Accordingly, TRAIL/Gln deprivation enhanced the expression of death receptor 5 (DR5) and transient knockdown of DR5 completely restored TRAIL/Gln deprivation-mediated apoptosis. Taken together, our results suggest that Gln deprivation conditions can be used for the development of new therapies for TRAIL-resistant cancers.
authors.affiliation: Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea.
authors.forename: Matharage Gayani
authors.initials: MG
authors.lastname: Dilshara
authors.affiliation: Anti-Aging Research Center, Dongeui University, Busan 47227, Republic of Korea.
authors.forename: Jin-Woo
authors.initials: JW
authors.lastname: Jeong
authors.affiliation: Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea; Department of Biological Sciences, Faculty of Applied Science, University of Rajarata, Mihintale 50300, Sri Lanka.
authors.forename: Rajapaksha Gedara
authors.initials: RG
authors.lastname: Prasad Tharanga Jayasooriya
authors.affiliation: Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea.
authors.forename: Ilandarage Menu
authors.initials: IM
authors.lastname: Neelaka Molagoda
authors.affiliation: Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea.
authors.forename: Seungheon
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea.
authors.forename: Sang Rul
authors.initials: SR
authors.lastname: Park
authors.affiliation: Department of Biochemistry, College of Oriental Medicine, Dong-Eui University, Busan 47227, Republic of Korea.
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
authors.affiliation: Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea. Electronic address: immunkim@jejunu.ac.kr.
authors.forename: Gi-Young
authors.initials: GY
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034622:RNA Interference; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism
chemical_list: C497249:DDIT3 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; D005973:Glutamine; D051742:Transcription Factor CHOP; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D053148:Caspase 3; D053453:Caspase 9
keywords: Apoptosis; CHOP; DR5; ER stress; Glutamine; TRAIL