Profiling and targeting of cellular mitochondrial bioenergetics: inhibition of human gastric cancer cell growth by carnosine.
Animals
Antineoplastic Agents
/ pharmacology
Carnosine
/ pharmacology
Cell Line, Tumor
Electron Transport Chain Complex Proteins
/ metabolism
Energy Metabolism
/ drug effects
Female
Humans
Mice, Nude
Mitochondria
/ drug effects
Mitochondrial Proteins
/ metabolism
Prohibitins
Proto-Oncogene Proteins c-akt
/ metabolism
Repressor Proteins
/ metabolism
Stomach Neoplasms
/ drug therapy
Xenograft Model Antitumor Assays
Akt
carnosine
human gastric cancer cells
mitochondrial bioenergetics
prohibitin-1 (PHB-1)
Journal
Acta pharmacologica Sinica
ISSN: 1745-7254
Titre abrégé: Acta Pharmacol Sin
Pays: United States
ID NLM: 100956087
Informations de publication
Date de publication:
Jul 2019
Jul 2019
Historique:
received:
02
04
2018
accepted:
07
10
2018
pubmed:
19
12
2018
medline:
14
1
2020
entrez:
19
12
2018
Statut:
ppublish
Résumé
L-Carnosine (β-alanyl-L-histidine) is a naturally occurring dipeptide distributed in various organs of mammalians. We previously showed that carnosine inhibited proliferation of human gastric cancer cells through targeting both mitochondrial bioenergetics and glycolysis pathway. But the mechanism underlying carnosine action on mitochondrial bioenergetics of tumor cells remains unclear. In the current study we investigated the effect of carnosine on the growth of human gastric cancer SGC-7901 cells in vitro and in vivo. We firstly showed that hydrolysis of carnosine was not a prerequisite for its anti-gastric cancer effect. Treatment of SGC-7901 cells with carnosine (20 mmol/L) significantly decreased the activities of mitochondrial respiratory chain complexes I-IV and mitochondrial ATP production, and downregulated 13 proteins involved in mitochondrial bioenergetics. Furthermore, carnosine treatment significantly suppressed the phosphorylation of Akt, while inhibition of Akt activation with GSK690693 significantly reduced the localization of prohibitin-1 (PHB-1) in the mitochondria of SGC-7901 and BGC-823 cells. In addition, we showed that silencing of PHB-1 gene with shRNA markedly reduced the mitochondrial PHB-1 in SGC-7901 cells, and significantly decreased the colony formation capacity and growth rate of the cells. In SGC-7901 cell xenograft nude mice, administration of carnosine (250 mg kg/d, ip, for 3 weeks) significantly inhibited the tumor growth and decreased the expression of mitochondrial PHB-1 in tumor tissue. Taken together, these results suggest that carnosine may act on multiple mitochondrial proteins to down-regulate mitochondrial bioenergetics and then to inhibit the growth and proliferation of SGC-7901 and BGC-823 cells.
Identifiants
pubmed: 30560903
doi: 10.1038/s41401-018-0182-8
pii: 10.1038/s41401-018-0182-8
pmc: PMC6786397
doi:
Substances chimiques
Antineoplastic Agents
0
Electron Transport Chain Complex Proteins
0
Mitochondrial Proteins
0
PHB protein, human
0
Prohibitins
0
Repressor Proteins
0
Carnosine
8HO6PVN24W
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
938-948Références
Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011;11:325–37.
doi: 10.1038/nrc3038
Jia D, Park JH, Jung KH, Levine H, Kaipparettu BA. Elucidating the metabolic plasticity of cancer: mitochondrial reprogramming and hybrid metabolic states. Cells. 2018;7:pii: E21.
doi: 10.3390/cells7030021
Diers AR, Broniowska KA, Chang CF, Hogg N. Pyruvate fuels mitochondrial respiration and proliferation of breast cancer cells: effect of monocarboxylate transporter inhibition. Biochem J. 2012;444:561–71.
doi: 10.1042/BJ20120294
Cheng G, Zielonka J, McAllister D, Tsai S, Dwinell MB, Kalyanaraman B. Profiling and targeting of cellular bioenergetics: inhibition of pancreatic cancer cell proliferation. Br J Cancer. 2014;111:85–93.
doi: 10.1038/bjc.2014.272
Kwiatkowski S, Kiersztan A, Drozak J. Biosynthesis of carnosine and related dipeptides in vertebrates. Curr Protein Pept Sci. 2018;19:771–89.
doi: 10.2174/1389203719666180226155657
Boldyrev AA. Problems and perspectives in studying the biological role of carnosine. Biochemistry (Mosc). 2000;65:751–6.
Ghodsi R, Kheirouri S. Carnosine and advanced glycation and products: a systematic review. Amino Acids. 2018;50:1177–86.
doi: 10.1007/s00726-018-2592-9
Horii Y, Shen J, Fujisaki Y, Yoshida K, Nagai K. Effects of L-carnosine on splenic sympathetic nerve activity and tumor proliferation. Neurosci Lett. 2012;510:1–5.
doi: 10.1016/j.neulet.2011.12.058
Shen Y, Yang J, Li J, Shi X, Ouyang L, Tian Y, et al. Carnosine inhibits the proliferation of human gastric cancer SGC-7901 cells through both of the mitochondrial respiration and glycolysis pathways. PLoS ONE. 2014;9:e104632.
doi: 10.1371/journal.pone.0104632
Shen Y, Tian Y, Yang J, Shi X, Ouyang L, Gao J, et al. Dual effects of carnosine on energy metabolism of cultured cortical astrocytes under normal and ischemic conditions. Regul Pept. 2014;192-193:45–52.
doi: 10.1016/j.regpep.2014.08.005
Shi L, Wang Y, Tu S, Li X, Sun M, Srivastava S, et al. The responses of mitochondrial proteome in rat liver to the consumption of moderate ethanol: the possible roles of aldo-keto reductases. J Proteome Res. 2008;7:3137–45.
doi: 10.1021/pr700853j
Spinazzi M, Casarin A, Pertegato V, Salviati L, Angelini C. Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells. Nat Protoc. 2012;7:1235–46.
doi: 10.1038/nprot.2012.058
Manfredi G, Yang L, Gajewski CD, Mattiazzi M. Measurements of ATP in mammalian cells. Methods. 2002;26:317–26.
doi: 10.1016/S1046-2023(02)00037-3
Renner C, Zemitzsch N, Fuchs B, Geiger KD, Hermes M, Hengstler J, et al. Carnosine retards tumor growth in vivo in an NIH3T3-HER2/neu mouse model. Mol Cancer. 2010;9:2.
doi: 10.1186/1476-4598-9-2
Artal-Sanz M, Tavernarakis N. Prohibitin and mitochondrial biology. Trends Endocrinol Metab. 2009;20:394–401.
doi: 10.1016/j.tem.2009.04.004
Peng YT, Chen P, Ouyang RY, Song L. Multifaceted role of prohibitin in cell survival and apoptosis. Apoptosis. 2015;20:1135–49.
doi: 10.1007/s10495-015-1143-z
Sasaki T, Kuniyasu H. Significance of AKT in gastric cancer. Int J Oncol. 2014;45:2187–92.
doi: 10.3892/ijo.2014.2678
Jiang L, Dong P, Zhang Z, Li C, Li Y, Liao Y, et al. Akt phosphorylates Prohibitin 1 to mediate its mitochondrial localization and promote proliferation of bladder cancer cells. Cell Death Dis. 2015;6:e1660.
doi: 10.1038/cddis.2015.40
Li J, Wang X, Hou J, Huang Y, Zhang Y, Xu W. Enhanced anticancer activity of 5-FU in combination with Bestatin: evidence in human tumor-derived cell lines and an H22 tumor-bearing mouse. Drug Discov Ther. 2015;9:45–52.
doi: 10.5582/ddt.2015.01006
Letzien U, Oppermann H, Meixensberger J, Gaunitz F. The antineoplastic effect of carnosine is accompanied by induction of PDK4 and can be mimicked by L-histidine. Amino Acids. 2014;46:1009–19.
doi: 10.1007/s00726-014-1664-8
Otani H, Okumura N, Hashida-Okumura A, Nagai K. Identification and characterization of a mouse dipeptidase that hydrolyzes L-carnosine. J Biochem. 2005;137:167–75.
doi: 10.1093/jb/mvi016
Hipkiss AR, Gaunitz F. Inhibition of tumour cell growth by carnosine: some possible mechanisms. Amino Acids. 2014;46:327–37.
doi: 10.1007/s00726-013-1627-5
Pathania D, Millard M, Neamati N. Opportunities in discovery and delivery of anticancer drugs targeting mitochondria and cancer cell metabolism. Adv Drug Deliv Rev. 2009;61:1250–75.
doi: 10.1016/j.addr.2009.05.010
Renner C, Asperger A, Seyffarth A, Meixensberger J, Gebhardt R, Gaunitz F. Carnosine inhibits ATP production in cells from malignant glioma. Neurol Res. 2010;32:101–5.
doi: 10.1179/016164109X12518779082237
Chowdhury I, Thompson WE, Thomas K. Prohibitins role in cellular survival through Ras-Raf-MEK-ERK pathway. J Cell Physiol. 2014;229:998–1004.
doi: 10.1002/jcp.24531
Osman C, Merkwirth C, Langer T. Prohibitins and the functional compartmentalization of mitochondrial membranes. J Cell Sci. 2009;122:3823–30.
doi: 10.1242/jcs.037655
Kang X, Zhang L, Sun J, Ni Z, Ma Y, Chen X, et al. Prohibitin: a potential biomarker for tissue-based detection of gastric cancer. J Gastroenterol. 2008;43:618–25.
doi: 10.1007/s00535-008-2208-3
Piechota J, Kolodziejczak M, Juszczak I, Sakamoto W, Janska H. Identification and characterization of high molecular weight complexes formed by matrix AAA proteases and prohibitins in mitochondria of Arabidopsis thaliana. J Biol Chem. 2010;285:12512–12512.
doi: 10.1074/jbc.M109.063644
Corona C, Frazzini V, Silvestri E, Lattanzio R, La Sorda R, Piantelli M, et al. Effects of dietary supplementation of carnosine on mitochondrial dysfunction, amyloid pathology, and cognitive deficits in 3xTg-AD mice. PLoS ONE. 2011;6:e17971.
doi: 10.1371/journal.pone.0017971
Hipkiss AR. Aging, proteotoxicity, mitochondria, glycation, NAD+ and carnosine: possible inter-relationships and resolution of the oxygen paradox. Front Aging Neurosci. 2010;2:10.
doi: 10.3389/fnagi.2010.00010