Abstract
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.
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References
Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat Rev Cancer. 2011;11:325–37.
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.
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.
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.
Kwiatkowski S, Kiersztan A, Drozak J. Biosynthesis of carnosine and related dipeptides in vertebrates. Curr Protein Pept Sci. 2018;19:771–89.
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.
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.
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.
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.
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.
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.
Manfredi G, Yang L, Gajewski CD, Mattiazzi M. Measurements of ATP in mammalian cells. Methods. 2002;26:317–26.
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.
Artal-Sanz M, Tavernarakis N. Prohibitin and mitochondrial biology. Trends Endocrinol Metab. 2009;20:394–401.
Peng YT, Chen P, Ouyang RY, Song L. Multifaceted role of prohibitin in cell survival and apoptosis. Apoptosis. 2015;20:1135–49.
Sasaki T, Kuniyasu H. Significance of AKT in gastric cancer. Int J Oncol. 2014;45:2187–92.
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.
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.
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.
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.
Hipkiss AR, Gaunitz F. Inhibition of tumour cell growth by carnosine: some possible mechanisms. Amino Acids. 2014;46:327–37.
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.
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.
Chowdhury I, Thompson WE, Thomas K. Prohibitins role in cellular survival through Ras-Raf-MEK-ERK pathway. J Cell Physiol. 2014;229:998–1004.
Osman C, Merkwirth C, Langer T. Prohibitins and the functional compartmentalization of mitochondrial membranes. J Cell Sci. 2009;122:3823–30.
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.
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.
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.
Hipkiss AR. Aging, proteotoxicity, mitochondria, glycation, NAD+ and carnosine: possible inter-relationships and resolution of the oxygen paradox. Front Aging Neurosci. 2010;2:10.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (81571289) and Key Discipline of Zhejiang Province in Medical Technology (First Class, Category A).
Author contributions:
YS and JXL conceived and designed the experiments; JYC, JBY, and YS wrote the manuscript; JYC and JBY performed experiments and analyzed the data; YL, MX, YYH, JJZ, and PC performed experiments.
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Cheng, Jy., Yang, Jb., Liu, Y. et al. Profiling and targeting of cellular mitochondrial bioenergetics: inhibition of human gastric cancer cell growth by carnosine. Acta Pharmacol Sin 40, 938–948 (2019). https://doi.org/10.1038/s41401-018-0182-8
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DOI: https://doi.org/10.1038/s41401-018-0182-8
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