Marine Cyclic Dipeptide Cyclo (L-Leu-L-Pro) Protects Normal Breast Epithelial Cells from tBHP-induced Oxidative Damage by Targeting CD151

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Deepak KGK
Seema Kumari
Rama Rao Malla


Actinobacteria; apoptosis, cytoprotective; DNA damage; MCF-12A cells


Background: Oxidative stress plays a key role in breast carcinogenesis. Cyclo (L-Leu-L-Pro) (CLP) is a homodetic cyclic dipeptide with 2,5-diketopiperazine scaffold isolated from marine actinobacteria. This study aimed to evaluate the protective activity of CLP and linear - (L-Leu-L-Pro) (LP) from tert-butyl hydroperoxide (tBHP)-induced damage using normal breast epithelial cell line model (MCF-12A).
Methods: The cytoprotective activity was evaluated by detecting the changes in intracellular ROS, mitochondrial superoxide, hydroxyl radical, hydrogen peroxide, and lipid peroxidation detection assays as well as cytotoxic assays of MTT, LDH assays and phase contrast microscopy. Genoprotective activity was evaluated by (Apurinic/Apyrimidinic) AP site, alkaline Comet, and 8-hydroxy-2-deoxyguanosine assays.
Results: The marine cyclic peptide, CLP, significantly protected MCF-12A cells by scavenging tBHP induced intracellular ROS such as super oxide, hydroxyl radicals and hydrogen peroxide, and by reducing the cytotoxicity and genotoxicity effect compared to LP. Moreover, the results showed that CD151 gene silencing by shRNA significantly reduced the overexpression of CD151, tBHP-induced ROS generation, cytotoxicity and genotoxicity in MCF-12A cells. The overexpression of CD151 caused increased levels of cytochrome P450, but was reduced following the application of CD151shRNA and CLP which led to elevated levels of intracellular ROS.
Conclusion: In the present study we noticed that CD151 gene silencing by shRNA and treatment with CLP have similar effects on reducing the intracellular ROS. This study uncovers the protective activity of CLP against a CD151-mediated oxidative stress-induced cellular damage. Our observations suggest that the anti-stress and anti-inflammation properties of CLP might have implications in cancer and are worth testing in cancer cell lines and tumor cells.


1. Cortes DF, Sha W, Hower V, Blekherman G, Laubenbacher R, Akman S, et al. Differential gene expression in normal and transformed human mammary epithelial cells in response to oxidative stress. Free Radic Biol Med. 2011;50(11):1565-74.
2. Zhao W, Feng H, Sun W, Liu K, Lu J-J, Chen X. Tert-butyl hydroperoxide (t-BHP) induced apoptosis and necroptosis in endothelial cells: Roles of NOX4 and mitochondrion. Redox biology. 2017;11:524-34.
3. Kucera O, Endlicher R, Rousar T, Lotkova H, Garnol T, Drahota Z, et al. The effect of tert-butyl hydroperoxide-induced oxidative stress on lean and steatotic rat hepatocytes in vitro. Oxidative medicine and cellular longevity. 2014;2014: 752506.
4. Ewald CY, Hourihan JM, Blackwell TK. Oxidative Stress Assays (arsenite and tBHP) in Caenorhabditis elegans. Bio-protocol. 2017;7(13):pii: e2365.
5. Kučera O, Endlicher R, Roušar T, Lotková H, Garnol T, Drahota Z, et al. The effect of tert-butyl hydroperoxide-induced oxidative stress on lean and steatotic rat hepatocytes in vitro. Oxidative medicine and cellular longevity. 2014;2014: 752506.
6. Kaur P, Kaur G, Bansal MP. Tertiary-butyl hydroperoxide induced oxidative stress and male reproductive activity in mice: role of transcription factor NF-kappaB and testicular antioxidant enzymes. Reprod Toxicol. 2006; 22(3):479-84.
7. Chen HH, Wang TC, Lee YC, Shen PT, Chang JY, Yeh TK, et al. Novel Nrf2/ARE activator, trans-Coniferylaldehyde, induces a HO-1-mediated defense mechanism through a dual p38α/MAPKAPK-2 and PK-N3 signaling pathway. Chem Res Toxicol. 2015;28(9):1681-92.
8. Taffe BG, Takahashi N, Kensler TW, Mason RP. Generation of free radicals from organic hydroperoxide tumor promoters in isolated mouse keratinocytes. Formation of alkyl and alkoxyl radicals from tert-butyl hydroperoxide and cumene hydroperoxide. J Biol Chem. 1987;262(25):12143-9.
9. Guyton KZ, Thompson JA, Kensler TW. Role of quinone methide in the in vitro toxicity of the skin tumor promoter butylated hydroxytoluene hydroperoxide. Chem Res Toxicol. 1993;6(5):731-8.
10. Müehlematter D, Ochi T, Cerutti P. Effects of tert-butyl hydroperoxide on promotable and non-promotable JB6 mouse epidermal cells. Chem Biol Interact. 1989;71(4):339-52.
11. Giordani A, Haigle J, Leflon P, Risler A, Salmon S, Aubailly M, et al. Contrasting effects of excess ferritin expression on the iron-mediated oxidative stress induced by tert-butyl hydroperoxide or ultraviolet-A in human fibroblasts and keratinocytes. J Photochem Photobiol B. 2000;54(1):43-54.
12. Kulak MV, Cyr AR, Woodfield GW, Bogachek M, Spanheimer PM, Li T, et al. Transcriptional regulation of the GPX1 gene by TFAP2C and aberrant CpG methylation in human breast cancer. Oncogene. 2013;32(34):4043-51.
13. Thompson JA, Bolton JL, Malkinson AM. Relationship between the metabolism of butylated hydroxytoluene (BHT) and lung tumor promotion in mice. Exp Lung Res. 1991;17(2): 439-53.
14. Lapshina E, Zavodnik I, Labieniec-Watala M, Rekawiecka K, Bryszewska M. Cytotoxic and genotoxic effects of tert-butyl hydroperoxide on Chinese hamster B14 cells. Mutation research. 2005;583:189-97.
15. +Seo GS, Jiang WY, Park PH, Sohn DH, Cheon JH, Lee SH. Hirsutenone reduces deterioration of tight junction proteins through EGFR/Akt and ERK1/2 pathway both converging to HO-1 induction. Biochem Pharmacol. 2014;90(2):115-25.
16. Huang RP, Peng A, Golard A, Hossain MZ, Huang R, Liu YG, et al. Hydrogen peroxide promotes transformation of rat liver non-neoplastic epithelial cells through activation of epidermal growth factor receptor. Mol Carcinog. 2001;30(4):209-17.
17. Kgk D, Kumari S, G S, Malla RR. Marine natural compound cyclo(L-leucyl-L-prolyl) peptide inhibits migration of triple negative breast cancer cells by disrupting interaction of CD151 and EGFR signaling. Chem Biol Interact. 2020;315:108872.
18. Nankivell P, Williams H, McConkey C, Webster K, High A, MacLennan K, et al. Tetraspanins CD9 and CD151, epidermal growth factor receptor and cyclooxygenase-2 expression predict malignant progression in oral epithelial dysplasia. British journal of cancer. 2013;109(11):2864-74.
19. Moribe H, Konakawa R, Koga D, Ushiki T, Nakamura K, Mekada E. Tetraspanin is required for generation of reactive oxygen species by the dual oxidase system in Caenorhabditis elegans. PLoS genetics. 2012;8(9):e1002957.
20. DeYulia GJ, Jr., Cárcamo JM. EGF receptor-ligand interaction generates extracellular hydrogen peroxide that inhibits EGFR-associated protein tyrosine phosphatases. Biochemical and biophysical research communications. 2005;334(1):38-42.
21.Moribe H, Mekada E. Co-occurrence of tetraspanin and ROS generators: Conservation in protein cross-linking and other developmental processes. Worm. 2013;2(2):e23415.
22.Mani B, Agarwal M, Katiyar-Agarwal S. Comprehensive Expression Profiling of Rice Tetraspanin Genes Reveals Diverse Roles During Development and Abiotic Stress. Frontiers in Plant Science. 2015;6(1088).
23. Wang L, Huang Z, Huang W, Chen X, Shan P, Zhong P, et al. Inhibition of epidermal growth factor receptor attenuates atherosclerosis via decreasing inflammation and oxidative stress. Scientific Reports. 2017;7(1):45917.
24. Chen TC, Sakaki T, Yamamoto K, Kittaka A. The roles of cytochrome P450 enzymes in prostate cancer development and treatment. Anticancer Res. 2012;32(1):291-8.
25.McFadyen MC, Melvin WT, Murray GI. Cytochrome P450 enzymes: novel options for cancer therapeutics. Mol Cancer Ther. 2004;3(3):363-71.
26. Ranjit S, Midde NM, Sinha N, Patters BJ, Rahman MA, Cory TJ, et al. Effect of Polyaryl Hydrocarbons on Cytotoxicity in Monocytic Cells: Potential Role of Cytochromes P450 and Oxidative Stress Pathways. PLoS One. 2016;11(9):e0163827.
27. Yang XJ, Lu HY, Li ZY, Bian Q, Qiu LL, Li Z, et al. Cytochrome P450 2A13 mediates aflatoxin B1-induced cytotoxicity and apoptosis in human bronchial epithelial cells. Toxicology. 2012;300(3):138-48.
28. Liu H, Baliga M, Baliga R. Effect of cytochrome P450 2E1 inhibitors on cisplatin-induced cytotoxicity to renal proximal tubular epithelial cells. Anticancer Res. 2002;22(2a):863-8.
29. Donatus IA, Sardjoko, Vermeulen NP. Cytotoxic and cytoprotective activities of curcumin. Effects on paracetamol-induced cytotoxicity, lipid peroxidation and glutathione depletion in rat hepatocytes. Biochem Pharmacol. 1990;39(12):1869-75.
30. Chen Q, Cederbaum AI. Cytotoxicity and apoptosis produced by cytochrome P450 2E1 in Hep G2 cells. Mol Pharmacol. 1998;53(4):638-48.
31. Caro AA, Cederbaum AI. Role of cytochrome P450 in phospholipase A2- and arachidonic acid-mediated cytotoxicity. Free Radic Biol Med. 2006;40(3):364-75.
32. Manikandan P, Nagini S. Cytochrome P450 Structure, Function and Clinical Significance: A Review. Curr Drug Targets. 2018;19(1):38-54.
33. Ye W, Chen R, Chen X, Huang B, Lin R, Xie X, et al. AhR regulates the expression of human cytochrome P450 1A1 (CYP1A1) by recruiting Sp1. Febs j. 2019;286(21):4215-31.
34. Morishima Y, Peng HM, Lin HL, Hollenberg PF, Sunahara RK, Osawa Y, et al. Regulation of cytochrome P450 2E1 by heat shock protein 90-dependent stabilization and CHIP-dependent proteasomal degradation. Biochemistry. 2005;44(49):16333-40.
35. Karthikeyan BS, Akbarsha MA, Parthasarathy S. Network analysis and cross species comparison of protein-protein interaction networks of human, mouse and rat cytochrome P450 proteins that degrade xenobiotics. Mol Biosyst. 2016;12(7):2119-34.
36. Praporski S, Ng SM, Nguyen AD, Corbin CJ, Mechler A, Zheng J, et al. Organization of cytochrome P450 enzymes involved in sex steroid synthesis. J Biol Chem. 2009;284(48):33224-32.
37. Zhang YJ, Gan RY, Li S, Zhou Y, Li AN, Xu DP, et al. Antioxidant Phytochemicals for the Prevention and Treatment of Chronic Diseases. Molecules (Basel, Switzerland). 2015;20(12): 21138-56.
38.Chakraborty K, Joy M, Chakkalakal SJ. Antioxidant and antiinflammatory secondary metabolites from the Asian green mussel Perna viridis. Journal of food biochemistry. 2019;43(3):e12736.
39. Abdelfattah MS, Elmallah MIY, Ebrahim HY, Almeer RS, Eltanany RMA, Abdel Moneim AE. Prodigiosins from a marine sponge-associated actinomycete attenuate HCl/ethanol-induced gastric lesion via antioxidant and anti-inflammatory mechanisms. PLoS One. 2019;14(6):e0216737.
40. Li X, Xia Z, Tang J, Wu J, Tong J, Li M, et al. Identification and Biological Evaluation of Secondary Metabolites from Marine Derived Fungi-Aspergillus sp. SCSIOW3, Cultivated in the Presence of Epigenetic Modifying Agents. Molecules (Basel, Switzerland). 2017;22(8).
41. Fuentes-Tristan S, Parra-Saldivar R, Iqbal HMN, Carrillo-Nieves D. Bioinspired biomolecules: Mycosporine-like amino acids and scytonemin from Lyngbya sp. with UV-protection potentialities. J Photochem Photobiol B. 2019;201:111684.
42.Subramani R, Aalbersberg W. Marine actinomycetes: an ongoing source of novel bioactive metabolites. Microbiological research. 2012;167(10):571-80.
43.Kang HK, Choi MC, Seo CH, Park Y. Therapeutic Properties and Biological Benefits of Marine-Derived Anticancer Peptides. International journal of molecular sciences. 2018;19(3).
44. Prasad C. Bioactive cyclic dipeptides. Peptides. 1995;16(1):151-64.
45. Martinez-Luis S, Gomez JF, Spadafora C, Guzman HM, Gutierrez M. Antitrypanosomal alkaloids from the marine bacterium Bacillus pumilus. Molecules (Basel, Switzerland). 2012;17(9):11146-55.
46. Li X, Dobretsov S, Xu Y, Xiao X, Hung OS, Qian PY. Antifouling diketopiperazines produced by a deep-sea bacterium, Streptomyces fungicidicus. Biofouling. 2006;22(3-4):201-8.
47. Wang N, Cui C-B, Li C-W. A new cyclic dipeptide penicimutide: the activated production of cyclic dipeptides by introduction of neomycin-resistance in the marine-derived fungus Penicilliumpurpurogenum G59. Archives of pharmacal research. 2016;39(6):762-70.
48. Ahmed EF, Hassan HM, Rateb ME, Abdel-Wahab N, Sameer S, Aly Taie HA, et al. A Comparative biochemical study on two marine endophytes, Bacterium SRCnm and Bacillus sp. JS, Isolated from red sea algae. Pakistan journal of pharmaceutical sciences. 2016;29(1):17-26.
49. Visamsetti A, Ramachandran SS, Kandasamy D. Penicillium chrysogenum DSOA associated with marine sponge (Tedania anhelans) exhibit antimycobacterial activity. Microbiological research. 2016;185:55-60.
50. Dong Y, Cui CB, Li CW, Hua W, Wu CJ, Zhu TJ, et al. Activation of dormant secondary metabolite production by introducing neomycin resistance into the deep-sea fungus, Aspergillus versicolor ZBY-3. Marine drugs. 2014;12(8):4326-52.
51.Magnusson J, Schnurer J. Lactobacillus coryniformis subsp. coryniformis strain Si3 produces a broad-spectrum proteinaceous antifungal compound. Applied and environmental microbiology. 2001;67(1):1-5.
52. Houston DR, Synstad B, Eijsink VG, Stark MJ, Eggleston IM, van Aalten DM. Structure-based exploration of cyclic dipeptide chitinase inhibitors. Journal of medicinal chemistry. 2004;47(23):5713-20.
53. Nicholson B, Lloyd GK, Miller BR, Palladino MA, Kiso Y, Hayashi Y, et al. NPI-2358 is a tubulin-depolymerizing agent: in-vitro evidence for activity as a tumor vascular-disrupting agent. Anti-cancer drugs. 2006;17(1):25-31.
54. Sinha S, Srivastava R, De Clercq E, Singh RK. Synthesis and antiviral properties of arabino and ribonucleosides of 1,3-dideazaadenine, 4-nitro-1,3-dideazapurine and diketopiperazine. Nucleosides, nucleotides & nucleic acids. 2004;23(12):1815-24.
55. Graz M, Hunt A, Jamie H, Grant G, Milne P. Antimicrobial activity of selected cyclic dipeptides. Die Pharmazie. 1999;54(10):772-5.
56. Kwon OS, Park SH, Yun BS, Pyun YR, Kim CJ. Cyclo(dehydroala-L-Leu), an alpha-glucosidase inhibitor from Penicillium sp. F70614. The Journal of antibiotics. 2000;53(9):954-8.
57. Nishanth Kumar S, Dileep C, Mohandas C, Nambisan B, Ca J. Cyclo(D-Tyr-D-Phe): a new antibacterial, anticancer, and antioxidant cyclic dipeptide from Bacillus sp. N strain associated with a rhabditid entomopathogenic nematode. Journal of peptide science. 2014;20(3):173-85.
58. Koo KB, Suh HJ, Ra KS, Choi JW. Protective effect of cyclo(his-pro) on streptozotocin-induced cytotoxicity and apoptosis in vitro. Journal of microbiology and biotechnology. 2011;21(2):218-27.
59. Tezgel Ö, Puchelle V, Du H, Illy N, Guégan P. Modification of proline‐based 2, 5‐diketopiperazines by anionic ring‐opening polymerization. Journal of Polymer Science Part A: Polymer Chemistry. 2019;57(9):1008-16.
60.Nilov DK, Yashina KI, Gushchina IV, Zakharenko AL, Sukhanova MV, Lavrik OI, et al. 2,5-Diketopiperazines: A New Class of Poly(ADP-ribose)polymerase Inhibitors. Biochemistry Biokhimiia. 2018;83(2):152-8.
61. Nagaseshu P, Gayatridevi V, Kumar A, Kumari S, Mohan M, Malla R. Antioxidant and antiproliferative potentials of marine actinomycetes. Int J Pharm Pharm Sci. 2016;8:277-84.
62. Pudi N, Varikuti GD, Badana AK, Gavara MM, Kumari S, Malla RJJAPS. Studies on optimization of growth parameters for enhanced production of antibiotic alkaloids by isolated marine actinomycetes. Journal of Applied Pharmaceutical Science. 2016;6(10):181-8.
63. Rhee KH. Isolation and characterization of Streptomyces sp KH-614 producing anti-VRE (vancomycin-resistant enterococci) antibiotics. The Journal of general and applied microbiology. 2002;48(6):321-7.
64. Su J, Zhong Y, Zeng L, Wu H, Shen X, Ma K. A new N-carboxyindole alkaloid from the marine sponge Rhaphisia pallida. Journal of natural products. 1996;59(5):504-6.
65. Yang L, Tan R-x, Wang Q, Huang W-y, Yin Y-x. Antifungal cyclopeptides from Halobacillus litoralis YS3106 of marine origin. Tetrahedron letters. 2002;43(37):6545-8.
66. Santos OC, Soares AR, Machado FL, Romanos MT, Muricy G, Giambiagi-deMarval M, et al. Investigation of biotechnological potential of sponge-associated bacteria collected in Brazilian coast. Letters in applied microbiology. 2015;60(2):140-7.
67. Ser HL, Palanisamy UD, Yin WF, Abd Malek SN, Chan KG, Goh BH, et al. Presence of antioxidative agent, Pyrrolo[1,2-a]pyrazine-1,4-dione, hexahydro- in newly isolated Streptomyces mangrovisoli sp. nov. Frontiers in microbiology. 2015;6:854.
68. Tan LT, Ser HL, Yin WF, Chan KG, Lee LH, Goh BH. Investigation of Antioxidative and Anticancer Potentials of Streptomyces sp. MUM256 Isolated from Malaysia Mangrove Soil. Frontiers in microbiology. 2015;6:1316.
69. Alshaibani M, Zin N, Jalil J, Sidik N, Ahmad SJ, Kamal N, et al. Isolation, Purification, and Characterization of Five Active Diketopiperazine Derivatives from Endophytic Streptomyces SUK 25 with Antimicrobial and Cytotoxic Activities. Journal of microbiology and biotechnology. 2017;27(7):1249-56.
70. Rhee KH. Cyclic dipeptides exhibit synergistic, broad spectrum antimicrobial effects and have anti-mutagenic properties. International journal of antimicrobial agents. 2004;24(5):423-7.
71. Gowrishankar S, Poornima B, Pandian SK. Inhibitory efficacy of cyclo(L-leucyl-L-prolyl) from mangrove rhizosphere bacterium-Bacillus amyloliquefaciens (MMS-50) toward cariogenic properties of Streptococcus mutans. Res Microbiol. 2014;165(4):278-89.
72. Kgk D, Kumari S, G S, Malla RR. Marine natural compound cyclo(L-leucyl-L-prolyl) peptide inhibits migration of triple negative breast cancer cells by disrupting interaction of CD151 and EGFR signaling. Chemico-biological interactions. 2019;315:108872.
73. Rao Malla R, Raghu H, Rao JS. Regulation of NADPH oxidase (Nox2) by lipid rafts in breast carcinoma cells. Int J Oncol. 2010;37(6):1483-93.
74. Jo Y-Y, Kim D-W, Choi J-Y, Kim S-G. 4-Hexylresorcinol and silk sericin increase the expression of vascular endothelial growth factor via different pathways. Scientific reports. 2019;9(1):3448.
75. Rosen GM, Pou S, Ramos CL, Cohen MS, Britigan BE. Free radicals and phagocytic cells. FASEB J. 1995;9(2):200-9.
76. Kwakye GF, Jiménez JA, Thomas MG, Kingsley BA, McIivin M, Saito MA, et al. Heterozygous huntingtin promotes cadmium neurotoxicity and neurodegeneration in striatal cells via altered metal transport and protein kinase C delta dependent oxidative stress and apoptosis signaling mechanisms. Neurotoxicology. 2019;70:48-61.
77. Kasetty G, Papareddy P, Kalle M, Rydengård V, Mörgelin M, Albiger B, et al. Structure-activity studies and therapeutic potential of host defense peptides of human thrombin. Antimicrob Agents Chemother. 2011;55(6):2880-90.
78. Vieira GLT, Lossie AC, Lay DC, Jr., Radcliffe JS, Garner JP. Preventing, treating, and predicting barbering: A fundamental role for biomarkers of oxidative stress in a mouse model of Trichotillomania. PLoS One. 2017;12(4):e0175222.
79. Bevara GB, Naveen Kumar AD, Koteshwaramma KL, Badana A, Kumari S, Malla RR. C-glycosyl flavone from Urginea indica inhibits proliferation & angiogenesis & induces apoptosis via cyclin-dependent kinase 6 in human breast, hepatic & colon cancer cell lines. Indian J Med Res. 2018;147(2):158-68.
80. Gayatri Devi V, Badana A, Kumari S, Nagaseshu P, Malla R. Therapeutic potentials of CD151 shRNA in targeting metastasis of triple negative breast cancer cell line MDA-MB-231. J Cancer Sci Ther. 2016;8(4):104-12.
81. Devi G, Badana A, Madhuri Ch MMP, Naik S. Knockdown of CD151 Gene Expression Reduces Survival of Estrogen Receptor Positive Breast Cancer Cells. J Clin Exp Oncol 6. 2017;4:2.
82. Comeau SR, Gatchell DW, Vajda S, Camacho CJ. ClusPro: a fully automated algorithm for protein-protein docking. Nucleic Acids Res. 2004;32(Web Server issue):W96-9.
83. Jiménez-García B, Pons C, Fernández-Recio J. pyDockWEB: a web server for rigid-body protein-protein docking using electrostatics and desolvation scoring. Bioinformatics. 2013;29(13):1698-9.
84. Conde de la Rosa L, Schoemaker MH, Vrenken TE, Buist-Homan M, Havinga R, Jansen PL, et al. Superoxide anions and hydrogen peroxide induce hepatocyte death by different mechanisms: involvement of JNK and ERK MAP kinases. Journal of hepatology. 2006;44(5):918-29.
85. Kim EH, Choi KS. A critical role of superoxide anion in selenite-induced mitophagic cell death. Autophagy. 2008;4(1):76-8.
86. Park S, Kim JA, Choi S, Suh SH. Superoxide is a potential culprit of caspase-3 dependent endothelial cell death induced by lysophosph-atidylcholine. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society. 2010;61(4):375-81.
87. Muller FL, Liu Y, Van Remmen H. Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem. 2004;279(47):49064-73.
88. Jastroch M, Divakaruni AS, Mookerjee S, Treberg JR, Brand MD. Mitochondrial proton and electron leaks. Essays in biochemistry. 2010;47:53-67.
89.Brand MD. Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling. Free Radic Biol Med. 2016;100:14-31.
90. Lu Y, Liu Y, Yang C. Evaluating In Vitro DNA Damage Using Comet Assay. J Vis Exp. 2017(128):56450.
91. Liu LX, Lu JC, Zeng HY, Cai JB, Zhang PF, Guo XJ, et al. Mortalin stabilizes CD151-depedent tetraspanin-enriched microdomains and implicates in the progression of hepatocellular carcinoma. Journal of Cancer. 2019;10(25):6199-206.
92. Koteswari LL, Kumari S, Kumar AB, Malla RR. A comparative anticancer study on procyanidin C1 against receptor positive and receptor negative breast cancer. Natural product research. 2019:1-8.
93. Kang JS, Choi IW, Han MH, Lee DS, Kim GY, Hwang HJ, et al. The Cytoprotective Effect of Petalonia binghamiae Methanol Extract against Oxidative Stress in C2C12 Myoblasts: Mediation by Upregulation of Heme Oxygenase-1 and Nuclear Factor-Erythroid 2 Related Factor 2. Marine drugs. 2015;13(5):2666-79.
94. Yagasaki M, Hashimoto S-i, biotechnology. Synthesis and application of dipeptides; current status and perspectives. Applied microbiology and biotechnology 2008;81(1):13.
95. Kaul S, Sharma SS, Mehta IK. Free radical scavenging potential of L-proline: evidence from in vitro assays. Amino acids. 2008;34(2):315-20.
96. Alia, Mohanty P, Matysik J. Effect of proline on the production of singlet oxygen. Amino acids. 2001;21(2):195-200.
97. Smirnoff N, Cumbes QJJP. Hydroxyl radical scavenging activity of compatible solutes. Phytochemistry. 1989;28(4):1057-60.
98. Phang JM, Donald SP, Pandhare J, Liu Y. The metabolism of proline, a stress substrate, modulates carcinogenic pathways. Amino acids. 2008;35(4):681-90.
99.Barbul A. Proline precursors to sustain Mammalian collagen synthesis. The Journal of nutrition. 2008;138(10):2021s-4s.
100.Wu G, Bazer FW, Burghardt RC, Johnson GA, Kim SW, Li XL, et al. Impacts of amino acid nutrition on pregnancy outcome in pigs: mechanisms and implications for swine production. Journal of animal science. 2010;88(13 Suppl):E195-204.
101.Giessen TW, Marahiel MA. Rational and combinatorial tailoring of bioactive cyclic dipeptides. Frontiers in microbiology. 2015;6:785.
102.Yan PS, Song Y, Sakuno E, Nakajima H, Nakagawa H, Yabe K. Cyclo(L-leucyl-L-prolyl) produced by Achromobacter xylosoxidans inhibits aflatoxin production by Aspergillus parasiticus. Applied and environmental microbiology. 2004;70(12):7466-73.
103.Zimmerman SS, Scheraga HA. Stability of cis, trans, and nonplanar peptide groups. Macromolecules. 1976;9(3):408-16.
104.Deslauriers R, Grzonka Z, Walter R. Influence of D and L amino-acid residues on the conformation of peptides in solution: A carbon-13 nuclear magnetic resonance study of cyclo(prolyl-leucyl). Biopolymers. 1976;15(9):1677-83.
105.Shimura H, Tanaka R, Shimada Y, Yamashiro K, Hattori N, Urabe T. Glycyl-alanyl-histidine protects PC12 cells against hydrogen peroxide toxicity. BMC biochemistry. 2017;18(1):14.
106.Kang M, Ryu J, Lee D, Lee MS, Kim HJ, Nam SH, et al. Correlations between transmembrane 4 L6 family member 5 (TM4SF5), CD151, and CD63 in liver fibrotic phenotypes and hepatic migration and invasive capacities. PLoS One. 2014;9(7):e102817.
107.Wadkin JCR, Patten DA, Kamarajah SK, Shepherd EL, Novitskaya V, Berditchevski F, et al. CD151 supports VCAM-1-mediated lymphocyte adhesion to liver endothelium and is upregulated in chronic liver disease and hepatocellular carcinoma. American journal of physiology Gastrointestinal and liver physiology. 2017;313(2):G138-g49.
108. Bae YS, Kang SW, Seo MS, Baines IC, Tekle E, Chock PB, et al. Epidermal growth factor (EGF)-induced generation of hydrogen peroxide Role in EGF receptor-mediated tyrosine phosphorylation. Journal of Biological Chemistry. 1997;272(1):217-21.

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