GHK, the Human Skin Remodeling Peptide, Induces Anti-Cancer Expression of Numerous Caspase, Growth Regulatory, and DNA Repair Genes


  • Loren Pickart Skin Biology, Bellevue, Washington 98006, USA
  • Jessica M. Vasquez-Soltero Skin Biology, Bellevue, Washington 98006, USA
  • Francoise D. Pickart Skin Biology, Bellevue, Washington 98006, USA
  • John Majnarich Bio Research Laboratories, Redmond, Washington 98052, USA



Copper peptides, cancer therapy, cancer inhibition, sarcoma, connectivity map.


 GHK (glycyl-L-histidyl-L-lysine) is a human plasma copper-binding peptide that declines during aging. Numerous studies have established many biological actions of GHK: it improves tissue regeneration, possesses anti-oxidant and anti-inflammatory effects, increases cellular stemness; increases decorin, angiogenesis, and nerve outgrowth. In recent studies, GHK was found to switch gene expression from a diseased state to a healthier state for certain cancers and for chronic obstructive pulmonary disease. In studies of aggressive, metastatic human colon cancer, the Broad Institute's Connectivity Map indicated that GHK, out of 1,309 bioactive molecules studied, reversed the expression of 70% of 54 genes over-expressed genes. GHK also reactivates programmed cell death in several cultured human cancer lines. To determine GHK's potential as a cancer treatment, we analyzed the molecule's effect on the human gene expression using the Connectivity Map. GHK induces a 50% or greater change of expression in 31.2% of human genes. GHK increased gene expression in 6 of the 12 human caspase genes that activate programmed cell death. In 28 other genes, GHK altered the pattern of gene expression in a manner that would be expected to inhibit cancer growth. For DNA repair genes, there was a one-sided increase in the expression of such genes (47 UP, 5 DOWN). A previous study found that a copper peptide plus ascorbic acid inhibited Ehrlich ascites cancer in mice. Using this method with GHK-copper gave a strong suppression of Sarcoma 180 in mice. These results support the idea that GHK may help to impede or suppress cancer growth.


Kheirelseid EA, Miller N, Chang KH, Nugent M, Kerin MJ. Clinical applications of gene expression in colorectal cancer. J Gastrointest Oncol 2013; 4: 144-57.

Claerhout S, Lim JY, Choi W, et al. Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer. PLoS One 2011; 6: e24662.

Pickart L, Freedman JH, Loker WJ, et al. Growth-modulating plasma tripeptide may function by facilitating copper uptake into cells. Nature 1980; 288: 715-7.

Pickart L. The human tri-peptide GHK and tissue remodeling. J Biomater Sci Polym Ed 2008; 19: 969-88.

Pickart L. The human tripeptide GHK (glycyl-l-histidyl-l-lysine), the copper switch, and the treatment of the degenerative conditions of aging. In: Klatz R, Goldman R, editors. Proceedings of the Anti-Aging Therapeutics XI; 2009: Chicago, Illinois: American Academy of Anti-Aging Medicine; 2009: p. 301-12.

Pickart L, Margolina A. Anti-aging activity of the GHK peptide - the skin and beyond. J Aging Res Clin Pr 2012; 1: 13-6.

Pickart L, Vasquez-Soltero JM, Margolina A. The human tripeptide GHK-Cu in prevention of oxidative stress and degenerative conditions of aging: implications for cognitive health. Oxid Med Cell Longev 2012; 2012: 324832.

Kang YA, Choi HR, Na JI, et al. Copper-GHK increases integrin expression and p63 positivity by keratinocytes. Arch Dermatol Res 2009; 301: 301-6.

Choi HR, Kang YA, Ryoo SJ, et al. Stem cell recovering effect of copper-free GHK in skin. J Pept Sci 2012; 18: 685-90. http: //

Campbell JD, McDonough JE, Zeskind JE, et al. A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK. Genome Med 2012; 4: 67.

Hong Y, Downey T, Eu KW, Koh PK, Cheah PY. A “metastasis-prone” signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics. Clin Exp Metastasis 2010; 27: 83-90.

Lamb J, Crawford ED, Peck D, et al. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science 2006; 313: 1929-35.

Matalka LE, Ford A, Unlap MT. The tripeptide, GHK, induces programmed cell death in SH-SY5Y neuroblastoma cells. J Biotechnol Biomater 2012; 2: 1-4.

Kimoto E, Tanaka H, Gyotoku J, Morishige F, Pauling L. Enhancement of antitumor activity of ascorbate against Ehrlich ascites tumor cells by the copper: glycylglycylhistidine complex. Cancer Res 1983; 43: 824-8.

Pickart L, Goodwin WH, Burgua W, Murphy TB, Johnson DK. Inhibition of the growth of cultured cells and an implanted fibrosarcoma by aroylhydrazone analogs of the Gly-His-Lys-Cu(II) complex. Biochem Pharmacol 1983; 32: 3868-71.

Simeon A, Wegrowski Y, Bontemps Y, Maquart FX. Expression of glycosaminoglycans and small proteoglycans in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu(2+). J Invest Dermatol 2000; 115: 962-8.

Jin T, Curry J, Smith P, Jiang J, Xiao TS. Structure of the NLRP1 caspase recruitment domain suggests potential mechanisms for its association with procaspase-1. Proteins 2013; 81: 1266-70.

NCBI [internet]. Bethesda, MD: National Center for Biotechnology Information, U.S. National Library of Medicine; [updated 2014 Apr 8; cited 2013 Aug 20]: Available from: http: //

NCBI [internet]. Bethesda, MD: National Center for Biotechnology Information, U.S. National Library of Medicine; [updated 2014 Apr 17; cited 2013 Aug 20]: Available from: http: //

Liu J, Chung HJ, Vogt M, et al. JTV1 co-activates FBP to induce USP29 transcription and stabilize p53 in response to oxidative stress. EMBO J 2011; 30: 846-58.

Eriksen KW, Sondergaard H, Woetmann A, et al. The combination of IL-21 and IFN-alpha boosts STAT3 activation, cytotoxicity and experimental tumor therapy. Mol Immunol 2009; 46: 812-20.

Zawacka-Pankau J, Kostecka A, Sznarkowska A, Hedstrom E, Kawiak A. p73 tumor suppressor protein: a close relative of p53 not only in structure but also in anti-cancer approach? Cell Cycle 2010; 9: 720-8.

Miyata N, Azuma T, Hozawa S, et al.Transforming growth factor beta and Ras/MEK/ERK signaling regulate the expression level of a novel tumor suppressor Lefty. Pancreas 2012; 41: 745-52.

Furuta S, Jeng YM, Zhou L, et al. IL-25 causes apoptosis of IL-25R-expressing breast cancer cells without toxicity to nonmalignant cells. Sci Transl Med 2011; 3: 78ra31.

Ochoa MC, Mazzolini G, Hervas-Stubbs S, de Sanmamed MF, Berraondo P, Melero I. Interleukin-15 in gene therapy of cancer. Curr Gene Ther 2013; 13: 15-30.

Kudoh T, Kimura J, Lu ZG, Miki Y, Yoshida K. D4S234E, a novel p53-responsive gene, induces apoptosis in response to DNA damage. Exp Cell Res 2010; 316: 2849-58.

NCBI [internet]. Bethesda, MD: National Center for Biotechnology Information, U.S. National Library of Medicine; [updated 2014 Apr 8; cited 2013 Aug 20]: Available from:

Huisman C, Wisman GB, Kazemier HG, et al. Functional validation of putative tumor suppressor gene C13ORF18 in cervical cancer by Artificial Transcription Factors. Mol Oncol 2013; 7: 669-79.

Aguissa-Toure AH, Wong RP, Li G. The ING family tumor suppressors: from structure to function. Cell Mol Life Sci 2011; 68: 45-54.

Vermeulen SJ, Nollet F, Teugels E, et al. The alphaE-catenin gene (CTNNA1) acts as an invasion-suppressor gene in human colon cancer cells. Oncogene 1999; 18: 905-15.

Larson PS, Schlechter BL, King CL, et al. CDKN1C/p57kip2 is a candidate tumor suppressor gene in human breast cancer. BMC Cancer 2008; 8: 68.

NCBI [internet]. Bethesda, MD: National Center for Biotechnology Information, U.S. National Library of Medicine; [updated 2014 Apr 8; cited 2013 Aug 20]: Available from:

Aoki K, Taketo MM. Adenomatous polyposis coli (APC): a multi-functional tumor suppressor gene. J Cell Sci 2007; 120: 3327-35.

Chu EC, Tarnawski AS. PTEN regulatory functions in tumor suppression and cell biology. Med Sci Monit 2004; 10: RA235-41.

Garcia-Cao I, Song MS, Hobbs RM, et al. Systemic elevation of PTEN induces a tumor-suppressive metabolic state. Cell 2012; 149: 49-62.

Chua YL, Ito Y, Pole JC, et al. The NRG1 gene is frequently silenced by methylation in breast cancers and is a strong candidate for the 8p tumour suppressor gene. Oncogene 2009; 28: 4041-52.

Dodd RD, Mito JK, Eward WC, et al. NF1 deletion generates multiple subtypes of soft-tissue sarcoma that respond to MEK inhibition. Mol Cancer Ther 2013; 12: 1906-17.

NCBI [internet]. Bethesda, MD: National Center for Biotechnology Information, U.S. National Library of Medicine; [updated 2014 Apr 21; cited 2013 Aug 20]: Available from:

Sofeu Feugaing DD, Gotte M, Viola M. More than matrix: the multifaceted role of decorin in cancer. Eur J Cell Biol 2013; 92: 1-11.

Silver DP, Livingston DM. Mechanisms of BRCA1 tumor suppression. Cancer Discov 2012; 2: 679-84.

Krech T, Scheuerer E, Geffers R, Kreipe H, Lehmann U, Christgen M. ABCB1/MDR1 contributes to the anticancer drug-resistant phenotype of IPH-926 human lobular breast cancer cells. Cancer Lett 2012; 315: 153-60.

Gu L, Vogiatzi P, Puhr M, et al. Stat5 promotes metastatic behavior of human prostate cancer cells in vitro and in vivo. Endocr Relat Cancer 2010; 17: 481-93.

Liao RG, Jung J, Tchaicha J, et al. Inhibitor-Sensitive FGFR2 and FGFR3 Mutations in Lung Squamous Cell Carcinoma. Cancer Res 2013; 73: 5195-205.

Besirli CG, Zheng QD, Reed DM, Zacks DN. ERK-mediated activation of Fas apoptotic inhibitory molecule 2 (Faim2) prevents apoptosis of 661W cells in a model of detachment-induced photoreceptor cell death. PLoS One 2012; 7: e46664.

Key TJ, Appleby PN, Reeves GK, Roddam AW. Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies. Lancet Oncol 2010; 11: 530-42.

Mocellin S, Nitti D. TNF and cancer: the two sides of the coin. Front Biosci 2008; 13: 2774-83.

Pollard JD, Quan S, Kang T, Koch RJ. Effects of copper tripeptide on the growth and expression of growth factors by normal and irradiated fibroblasts. Arch Facial Plast Surg 2005; 7: 27-31.

Iorio F, Bosotti R, Scacheri E, et al. Discovery of drug mode of action and drug repositioning from transcriptional responses. Proc Natl Acad Sci USA 2010; 107: 14621-6.

Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M, Alt FW. DNA repair, genome stability, and aging. Cell 2005; 120: 497-512.

Wolters S, Schumacher B. Genome maintenance and transcription integrity in aging and disease. Front Genet 2013; 4: 19.

Diderich K, Alanazi M, Hoeijmakers JH. Premature aging and cancer in nucleotide excision repair-disorders. DNA Repair Amst 2011; 10: 772-80.

Smakhtin MY, Konoplya AI, Severyanova LA, Kurtseva AA, Cherdakov VY. Reparative activity of different functional group peptides in hepatopathyes. Exp Biol Med 2006; 3: 11-7.

Cherdakov VY, Smakhtin MY, Dubrovin GM, Dudka VT, Bobyntsev II. Synergetic antioxidant and reparative action of thymogen, dalargin and peptide Gly-His-Lys in tubular bone fractures. Exp Biol Med 2010; 4: 15-20.

Hostynek JJ, Dreher F, Maibach HI. Human skin penetration of a copper tripeptide in vitro as a function of skin layer. Inflamm Res 2011; 60: 79-86.

Li P, Nielsen HM, Mullertz A. Oral delivery of peptides and proteins using lipid-based drug delivery systems. Expert Opin Drug Deliv 2012; 9: 1289-304.

Swaminathan J, Ehrhardt C. Liposomal delivery of proteins and peptides. Expert Opin Drug Deliv 2012; 9: 1489-503.




How to Cite

Loren Pickart, Jessica M. Vasquez-Soltero, Francoise D. Pickart, & John Majnarich. (2014). GHK, the Human Skin Remodeling Peptide, Induces Anti-Cancer Expression of Numerous Caspase, Growth Regulatory, and DNA Repair Genes. Journal of Analytical Oncology, 3(2),  79–87.