Loss of RACK1 promotes glutamine addiction via activating AKT/mTOR/ASCT2 axis to facilitate tumor growth in gastric cancer.
ASCT2
Autophagy
Gastric cancer
Glutamine addiction
RACK1
Journal
Cellular oncology (Dordrecht)
ISSN: 2211-3436
Titre abrégé: Cell Oncol (Dordr)
Pays: Netherlands
ID NLM: 101552938
Informations de publication
Date de publication:
14 Aug 2023
14 Aug 2023
Historique:
accepted:
31
07
2023
medline:
14
8
2023
pubmed:
14
8
2023
entrez:
14
8
2023
Statut:
aheadofprint
Résumé
Metabolic reprogramming is closely related to the development of gastric cancer (GC), which remains as the fourth leading cause of cancer-related death worldwide. As a tumor suppressor for GC, whether receptor for activated C-kinase 1 (RACK1) play a modulatory role in metabolic reprogramming remains largely unclear. GC cell lines and cell-derived xenograft mouse model were used to identify the biological function of RACK1. Flow cytometry and Seahorse assays were applied to examine cell cycle and oxygen consumption rate (OCR), respectively. Western blot, real-time PCR and autophagy double fluorescent assays were utilized to explore the signaling. Immunohistochemistry was performed to detect the expression of RACK1 and other indicators in tissue sections. Loss of RACK1 facilitated the viability, colony formation, cell cycle progression and OCR of GC cells in a glutamine-dependent manner. Further investigation revealed that RACK1 knockdown inhibited the lysosomal degradation of Alanine-serine-cysteine amino acid transporter 2 (ASCT2). Mechanistically, depletion of RACK1 remarkably decreased PTEN expression through up-regulating miR-146b-5p, leading to the activation of AKT/mTOR signaling pathway which dampened autophagy flux subsequently. Moreover, knockdown of ASCT2 could reverse the promotive effect of RACK1 depletion on GC tumor growth both in vitro and in vivo. Tissue microarray confirmed that RACK1 was negatively correlated with the expression of ASCT2 and p62, as well as the phosphorylation of mTOR. Together, our results demonstrate that the suppressive function of RACK1 in GC is associated with ASCT2-mediated glutamine metabolism, and imply that targeting RACK1/ASCT2 axis provides potential strategies for GC treatment.
Sections du résumé
BACKGROUND
BACKGROUND
Metabolic reprogramming is closely related to the development of gastric cancer (GC), which remains as the fourth leading cause of cancer-related death worldwide. As a tumor suppressor for GC, whether receptor for activated C-kinase 1 (RACK1) play a modulatory role in metabolic reprogramming remains largely unclear.
METHODS
METHODS
GC cell lines and cell-derived xenograft mouse model were used to identify the biological function of RACK1. Flow cytometry and Seahorse assays were applied to examine cell cycle and oxygen consumption rate (OCR), respectively. Western blot, real-time PCR and autophagy double fluorescent assays were utilized to explore the signaling. Immunohistochemistry was performed to detect the expression of RACK1 and other indicators in tissue sections.
RESULTS
RESULTS
Loss of RACK1 facilitated the viability, colony formation, cell cycle progression and OCR of GC cells in a glutamine-dependent manner. Further investigation revealed that RACK1 knockdown inhibited the lysosomal degradation of Alanine-serine-cysteine amino acid transporter 2 (ASCT2). Mechanistically, depletion of RACK1 remarkably decreased PTEN expression through up-regulating miR-146b-5p, leading to the activation of AKT/mTOR signaling pathway which dampened autophagy flux subsequently. Moreover, knockdown of ASCT2 could reverse the promotive effect of RACK1 depletion on GC tumor growth both in vitro and in vivo. Tissue microarray confirmed that RACK1 was negatively correlated with the expression of ASCT2 and p62, as well as the phosphorylation of mTOR.
CONCLUSION
CONCLUSIONS
Together, our results demonstrate that the suppressive function of RACK1 in GC is associated with ASCT2-mediated glutamine metabolism, and imply that targeting RACK1/ASCT2 axis provides potential strategies for GC treatment.
Identifiants
pubmed: 37578594
doi: 10.1007/s13402-023-00854-1
pii: 10.1007/s13402-023-00854-1
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : National Natural Science Fund
ID : 82103535, 82273385, 82073245, 32271337
Organisme : National Natural Science Fund
ID : 82103535, 82273385, 82073245, 32271337
Organisme : National Natural Science Fund
ID : 82103535, 82273385, 82073245, 32271337
Informations de copyright
© 2023. Springer Nature Switzerland AG.
Références
S.H. Jeong, J.K. Lee, K.W. Seo, J.S. Min, J. Clin. Med. 12, (2023). https://doi.org/10.3390/jcm12123880
H. Sung, J. Ferlay, R.L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, F. Bray, CA Cancer J. Clin. 71, 209–249 (2021). https://doi.org/10.3322/caac.21660
doi: 10.3322/caac.21660
pubmed: 33538338
A.D. Wagner, S. Unverzagt, W. Grothe, G. Kleber, A. Grothey, J. Haerting, W.E. Fleig, Cochrane Database Syst. Rev., CD004064 (2010). https://doi.org/10.1002/14651858.CD004064.pub3
D. Tartaglia, A. Bertolucci, C. Galatioto, M. Palmeri, G. Di Franco, R. Fantacci, N. Furbetta, M. Chiarugi, Int. J. Surg. 28, 149–152 (2016). https://doi.org/10.1016/j.ijsu.2016.02.085
doi: 10.1016/j.ijsu.2016.02.085
pubmed: 26931338
S. Sunkar, D. Neeharaika, J. Nellore, V.C. Nachiyar, S. Peela, Crit. Rev. Oncog. 25, 311–333 (2020). https://doi.org/10.1615/CritRevOncog.2020036206
doi: 10.1615/CritRevOncog.2020036206
pubmed: 33639060
H. Wu, S. Song, A. Yan, X. Guo, L. Chang, L. Xu, L. Hu, M. Kuang, B. Liu, D. He, R. Zhao, L. Wang, X. Wu, J. Gu, Y. Ruan, Cancer Lett. 469, 287–300 (2020). https://doi.org/10.1016/j.canlet.2019.11.002
doi: 10.1016/j.canlet.2019.11.002
pubmed: 31705928
D.R. Adams, D. Ron, P.A. Kiely, Cell Commun. Signal. 9, 22 (2011). https://doi.org/10.1186/1478-811X-9-22
doi: 10.1186/1478-811X-9-22
pubmed: 21978545
pmcid: 3195729
X.-X. Cao, J.-D. Xu, X.-L. Liu, J.-W. Xu, W.-J. Wang, Q.-Q. Li, Q. Chen, Z.-D. Xu, X.-P. Liu, Int. J. Cancer 127, 1172–1179 (2010). https://doi.org/10.1002/ijc.25120
doi: 10.1002/ijc.25120
pubmed: 20020495
S. Shi, Y.-Z. Deng, J.-S. Zhao, X.-D. Ji, J. Shi, Y.-X. Feng, G. Li, J.-J. Li, D. Zhu, H.P. Koeffler, Y. Zhao, D. Xie, J. Biol. Chem. 287, 7845–7858 (2012). https://doi.org/10.1074/jbc.M111.315416
doi: 10.1074/jbc.M111.315416
pubmed: 22262830
pmcid: 3318742
R. Nagashio, Y. Sato, T. Matsumoto, T. Kageyama, Y. Satoh, R. Shinichiro, N. Masuda, N. Goshima, S.-X. Jiang, I. Okayasu, Lung Cancer (Amsterdam, Netherlands) 69, 54–59 (2010). https://doi.org/10.1016/j.lungcan.2009.09.015
doi: 10.1016/j.lungcan.2009.09.015
pubmed: 19892429
Y. Ruan, L. Sun, Y. Hao, L. Wang, J. Xu, W. Zhang, J. Xie, L. Guo, L. Zhou, X. Yun, H. Zhu, A. Shen, J. Gu, J. Clin. Investig. 122, 2554–2566 (2012). https://doi.org/10.1172/JCI58488
doi: 10.1172/JCI58488
pubmed: 22653060
pmcid: 3386807
F. Duan, H. Wu, D. Jia, W. Wu, S. Ren, L. Wang, S. Song, X. Guo, F. Liu, Y. Ruan, J. Gu, J. Hepatol. 68, 1191–1202 (2018). https://doi.org/10.1016/j.jhep.2018.02.003
doi: 10.1016/j.jhep.2018.02.003
pubmed: 29454068
J. Feng, L. Xie, R. Kong, Y. Zhang, K. Shi, W. Lu, H. Jiang, Int. J. Mol. Med. 40, 1965–1970 (2017). https://doi.org/10.3892/ijmm.2017.3154
doi: 10.3892/ijmm.2017.3154
pubmed: 29039466
L. Chen, L. Min, X. Wang, J. Zhao, H. Chen, J. Qin, W. Chen, Z. Shen, Z. Tang, Q. Gan, Y. Ruan, Y. Sun, X. Qin, J. Gu, Cancer Res. 75, 3832–3841 (2015). https://doi.org/10.1158/0008-5472.CAN-14-3690
doi: 10.1158/0008-5472.CAN-14-3690
pubmed: 26199092
Y. Hu, J.P. Liu, X.Y. Li, Y. Cai, C. He, N.S. Li, C. Xie, Z.J. Xiong, Z.M. Ge, N.H. Lu, Y. Zhu, Cancer Lett. 450, 144–154 (2019). https://doi.org/10.1016/j.canlet.2019.02.039
doi: 10.1016/j.canlet.2019.02.039
pubmed: 30849478
Z. Qu, J. Zhou, Y. Zhou, Y. Xie, Y. Jiang, J. Wu, Z. Luo, G. Liu, L. Yin, X.L. Zhang, Sci. Adv. 6, (2020). https://doi.org/10.1126/sciadv.aba4733
P.S. Ward, C.B. Thompson, Cancer Cell 21, 297–308 (2012). https://doi.org/10.1016/j.ccr.2012.02.014
doi: 10.1016/j.ccr.2012.02.014
pubmed: 22439925
pmcid: 3311998
D.S. Wishart, EBioMedicine 2, 478–479 (2015). https://doi.org/10.1016/j.ebiom.2015.05.022
doi: 10.1016/j.ebiom.2015.05.022
pubmed: 26288805
pmcid: 4535307
C. Laezza, A. D’Alessandro, L. Di Croce, P. Picardi, E. Ciaglia, S. Pisanti, A.M. Malfitano, M. Comegna, R. Faraonio, P. Gazzerro, M. Bifulco, Cell Death Dis. 6, e1909 (2015). https://doi.org/10.1038/cddis.2015.279
doi: 10.1038/cddis.2015.279
pubmed: 26469958
pmcid: 4632304
M.G. Vander Heiden, L.C. Cantley, C.B. Thompson, Science (New York, N.Y.) 324, 1029–1033 (2009). https://doi.org/10.1126/science.1160809
doi: 10.1126/science.1160809
pubmed: 19460998
Q. Zhou, W. Lin, C. Wang, F. Sun, S. Ju, Q. Chen, Y. Wang, Y. Chen, H. Li, L. Wang, Z. Hu, H. Jin, X. Wang, Y. Sun, Nat. Commun. 13, 3034 (2022). https://doi.org/10.1038/s41467-022-30559-2
doi: 10.1038/s41467-022-30559-2
pubmed: 35641493
pmcid: 9156729
J.Z. Lin, N. Lin, W.J. Zhao, J. Cell. Biochem. (2023). https://doi.org/10.1002/jcb.30444
doi: 10.1002/jcb.30444
pubmed: 37475541
L.-L. Li, L. Wei, N. Zhang, W.-Y. Wei, C. Hu, W. Deng, Q.-Z. Tang, Biomed. Res. Int. 2020, 8593617 (2020). https://doi.org/10.1155/2020/8593617
doi: 10.1155/2020/8593617
pubmed: 32596387
pmcid: 7298255
J. Ramírez-Moya, L. Wert-Lamas, P. Santisteban, Oncogene 37, 3369–3383 (2018). https://doi.org/10.1038/s41388-017-0088-9
doi: 10.1038/s41388-017-0088-9
pubmed: 29353884
Y. Wang, Y. Xia, Z. Lu, Cancer Commun. (Lond.) 38, 65 (2018). https://doi.org/10.1186/s40880-018-0335-7
doi: 10.1186/s40880-018-0335-7
pubmed: 30376896
J. Zhang, N.N. Pavlova, C.B. Thompson, EMBO J. 36, 1302–1315 (2017). https://doi.org/10.15252/embj.201696151
doi: 10.15252/embj.201696151
pubmed: 28420743
pmcid: 5430235
L. Chen, H. Cui, Int. J. Mol. Sci. 16, 22830–22855 (2015). https://doi.org/10.3390/ijms160922830
doi: 10.3390/ijms160922830
pubmed: 26402672
pmcid: 4613338
H. Jiang, N. Zhang, T. Tang, F. Feng, H. Sun, W. Qu, Pharmacol. Res. 158, 104844 (2020). https://doi.org/10.1016/j.phrs.2020.104844
doi: 10.1016/j.phrs.2020.104844
pubmed: 32438035
U. Kahya, A.S. Köseer, A. Dubrovska, Cancers (Basel) 13, (2021). https://doi.org/10.3390/cancers13010125
N.E. Avissar, H.C. Sax, L. Toia, Dig. Dis. Sci. 53, 2113–2125 (2008)
doi: 10.1007/s10620-007-0120-y
pubmed: 18157695
H. Zhou, M. Yuan, Q. Yu, X. Zhou, W. Min, D. Gao, Cancer Biomark. 17, (2016). https://doi.org/10.3233/CBM-160613
S. Erbil, O. Oral, G. Mitou, C. Kig, E. Durmaz-Timucin, E. Guven-Maiorov, F. Gulacti, G. Gokce, J. Dengjel, O.U. Sezerman, D. Gozuacik, J Biol Chem 291, 16753–16765 (2016). https://doi.org/10.1074/jbc.M115.708081
doi: 10.1074/jbc.M115.708081
pubmed: 27325703
pmcid: 4974388
Y. Zhao, Q. Wang, G. Qiu, S. Zhou, Z. Jing, J. Wang, W. Wang, J. Cao, K. Han, Q. Cheng, B. Shen, Y. Chen, W.J. Zhang, Y. Ma, J. Zhang, Cell Rep. 13, 1407–1417 (2015). https://doi.org/10.1016/j.celrep.2015.10.011
doi: 10.1016/j.celrep.2015.10.011
pubmed: 26549445
Y.C. Kim, K.-L. Guan, J. Clin. Invest. 125, 25–32 (2015). https://doi.org/10.1172/JCI73939
doi: 10.1172/JCI73939
pubmed: 25654547
pmcid: 4382265
B.J. Altman, Z.E. Stine, C.V. Dang, Nat. Rev. Cancer 16, 619–634 (2016). https://doi.org/10.1038/nrc.2016.71
doi: 10.1038/nrc.2016.71
pubmed: 27492215
pmcid: 5484415
M.J. Lukey, W.P. Katt, R.A. Cerione, Drug Discov. Today 22, 796–804 (2017). https://doi.org/10.1016/j.drudis.2016.12.003
doi: 10.1016/j.drudis.2016.12.003
pubmed: 27988359
M. Tang, T. Xiong, Cell. Div. 18, 4 (2023). https://doi.org/10.1186/s13008-023-00083-w
doi: 10.1186/s13008-023-00083-w
pubmed: 36882799
pmcid: 9993666
L. He, J. Guo, Z. Fan, S. Yang, C. Zhang, B. Cheng, J. Xia, Cell. Signal. 106, 110635 (2023). https://doi.org/10.1016/j.cellsig.2023.110635
doi: 10.1016/j.cellsig.2023.110635
pubmed: 36813147
S. Mehta, J. Moon, M. Hashmi, M. Leblanc, C.H. Huang, E. Rinehart, G.T. Wolf, S.G. Urba, S.K. Banerjee, S. Williamson, Oncol. Rep. 29, 2095–2100 (2013). https://doi.org/10.3892/or.2013.2374
doi: 10.3892/or.2013.2374
pubmed: 23563900
pmcid: 3694610
A. Ivagnes, M. Messaoudene, G. Stoll, B. Routy, A. Fluckiger, T. Yamazaki, K. Iribarren, C.P.M. Duong, L. Fend, A. Caignard, I. Cremer, A. LeCesne, J. Adam, C. Honore, O. Mir, L. Chaigneau, A. Berger, P. Validire, C. Christidis, V.L. Brun-Ly, M.J. Smyth, X. Mariette, B.L. Salomon, G. Kroemer, S. Rusakiewicz, L. Zitvogel, Oncoimmunology 7, e1386826 (2018). https://doi.org/10.1080/2162402X.2017.1386826
doi: 10.1080/2162402X.2017.1386826
pubmed: 30524877