Curcumin counteracts the proliferative effect of estradiol and induces apoptosis in cervical cancer cells


Cervical cancer is the most common cancer in Indian females and is associated with infection with high-risk Human papilloma viruses (HPVs) which encode viral oncoprotein E6 and E7. Estradiol has been established as a risk factor for cervical cancer and has been shown to play a synergistic role with viral oncoproteins. Curcumin (Diferuloyl methane), a chemopreventive agent, is a natural compound extracted from Curcuma longa that allows suppression and retardation of carcinogenesis in many types of cancer and is currently being tested in various human clinical trials as it has been found to be well tolerated at higher doses with a relatively well established safety profile. The objective of this study was to test the effect of curcumin on HPV-positive and negative cervical cancer cell lines HeLa, SiHa, CaSki, and C33A pretreated with estradiol. It was found that HPV-positive cells pretreated with estradiol show reduced apoptosis as compared to curcumin by itself. However, curcumin was able to counteract the proliferative response of estradiol, and induce apoptosis. There was no difference in percentage apoptosis as compared to estradiol pretreatment in HPV-negative cell line C33A. Molecular studies showed elevation of Telomerase, viral oncoproteins E6 and E7, PCNA, p16, Cyclin D1 in HPV-positive cell lines on treatment with estradiol but after treatment with curcumin the level of E7, PCNA, and Cyclin D1 was reduced but the level of E6, Telomerase, and p16 was unaltered. Furthermore, estradiol-pretreated HPV-negative cell line C33A showed reduction in level of Telomerase, PCNA, p16, and activation of both p53 and p73 tumor suppressor proteins, thus, demonstrating the importance of E6 in estradiol-mediated protective effect.

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  1. 1.

    Dehn D, Torkko KC, Shroyer RK (2007) Human papillomavirus testing and molecular markers of cervical dysplasia and carcinoma. Cancer (Cancer Cytopathol) 111(1):1–14

    CAS  Google Scholar 

  2. 2.

    Moreno V, Bosch FX, Munoz N, The International Agency for Research on Cancer Multicentric Cervical Cancer Study Group et al (2002) Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study. Lancet 359:1085–1092

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Munoz N, Franceschi S, Bosetti C, The International Agency for Research on Cancer Multicentric Cervical Cancer Study Group et al (2002) Role of parity and human papillomavirus in cervical cancer: the IARC multicentric case-control study. Lancet 359:1093–1101

    Article  PubMed  Google Scholar 

  4. 4.

    Castellsague X, Diaz M, de Sanjose S, The International Agency for Research on Cancer Multicenter Cervical Cancer Study Group et al (2006) Worldwide human papillomavirus etiology of cervical adenocarcinoma and its cofactors: implications for screening and prevention. J Natl Cancer Inst 98:303–315

    Article  PubMed  Google Scholar 

  5. 5.

    Kim CJ, Um SJ, Kim TY et al (2000) Regulation of cell growth and HPV genes by exogenous estrogen in cervical cancer cells. Int J Gynecol Cancer 10:157–164

    Article  PubMed  Google Scholar 

  6. 6.

    Kedzia W, Gozdzicka-Jozefiak A, Kwasniewska A, Schmidt M, Miturski R, Spaczynski M (2000) Relationship between HPV infection of the cervix and blood serum levels of steroid hormones among pre- and postmenopausal women. Eur J Gynaecol Oncol 21:177–179

    CAS  PubMed  Google Scholar 

  7. 7.

    Auborn KJ, Woodworth C, DiPaolo JA, Bradlow HL (1991) The interaction between HPV infection and estrogen metabolism in cervical carcinogenesis. Int J Cancer 49:867–869

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Deligeoroglou E, Michailidis E, Creatsas G (2003) Oral contraceptives and reproductive system cancer. Ann N Y Acad Sci 997:199–208

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Salazar EL, Sojo-Aranda I, Lopez R, Salcedo M (2001) The evidence for an etiological relationship between oral contraceptive use and dysplastic change in cervical tissue. Gynecol Endocrinol 15:23–28

    CAS  PubMed  Google Scholar 

  10. 10.

    Herbst AL, Ulfelder H, Poskanzer DC (1971) Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 284:878–881

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Arbeit JM, Howley PM, Hanahan D (1996) Chronic estrogen-induced cervical and vaginal squamous carcinogenesis in human papillomavirus type 16 transgenic mice. Proc Natl Acad Sci USA 93:2930–2935

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Anand P, Sundaram C, Jhurani S, Kunnumakkara AB, Aggarwal BB (2008) Curcumin and cancer: an “old-age” disease with an “age-old” solution. Cancer Lett 267:133–164

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Singh M, Sharma H, Singh N (2007) Hydrogen peroxide induces apoptosis in HeLa cells through mitochondrial pathway. Mitochondrion 7:367–373

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Khanna N, Sen S, Sharma H, Singh N (2003) S29 ribosomal protein induces apoptosis in H520 cells and sensitizes them to chemotherapy. Biochem Biophys Res Commun 304:26–35

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Sen S, Sharma H, Singh N (2005) Curcumin enhances Vinorelbine mediated apoptosis in NSCLC cells by the mitochondrial pathway. Biochem Biophys Res Commun 331:1245–1252

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Singh M, Singh N (2008) Induction of apoptosis in HPV 16 positive cervical cancer cell lines: involvement of mitochondrial pathway. Mol Cell Biochem 310:57–65

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Castellsagué X (2008) Natural history and epidemiology of HPV infection and cervical cancer. Gynecol Oncol 110(3):4–7

    Article  Google Scholar 

  18. 18.

    Pater MM, Mittal R, Pater A (1994) Role of steroid hormones in potentiating transformation of cervical cells by human papillomaviruses. Trends Microbiol 2(7):229–234

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Moodley M, Moodley J, Chetty R, Herrington CS (2003) The role of steroid contraceptive hormones in the pathogenesis of invasive cervical cancer: a review. Int J Gynecol Cancer 13(2):103–110

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Divya CS, Pillai MR (2006) Antitumor action of curcumin in human papillomavirus associated cells involves downregulation of viral oncogenes, prevention of NFkB and AP-1 translocation, and modulation of apoptosis. Mol Carcinog 45(5):320–332

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Shay JW, Wright WE (2006) Telomerase therapeutics for cancer; challenge and the new directions. Nat Rev Drug Discovery 5:577–584

    CAS  Article  Google Scholar 

  22. 22.

    Jaio MU, Wei XL (2002) Telomere and telomerase in oncology. Cell Res 12(1):1–7

    Article  Google Scholar 

  23. 23.

    Keating JT, Cviko A, Riethdorf S et al (2001) Ki-67, cyclin E, and p16INK4 are complementary surrogate biomarkers for human papilloma virus-related cervical neoplasia. Am J Surg Pathol 25:884–891

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    Klaes R, Friedrich T, Spitkovsky D et al (2001) Overexpression of p16(INK4A) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer 92:276–284

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Aaltomaa S, Lipponen P, Syrjanen K (1993) Proliferating cell nuclear antigen (PCNA) immunolabeling as a prognostic factor in axillary lymph node negative breast cancer. Anticancer Res 13:533–538

    CAS  PubMed  Google Scholar 

  26. 26.

    Bourdeau V, Deschenes J, Metivier R, Nagai Y, Nguyen D et al (2004) Genome-wide identification of high-affinity estrogen response elements in human and mouse. Mol Endocrinol 18:1411–1427

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Schultz-Norton JR, Gabisi VA, Ziegler YS, McLeod IX, Yates JR et al (2007) Interaction of estrogen receptor alpha with proliferating cell nuclear antigen. Nucleic Acids Res 35:5028–5038

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Stacey DW (2003) Cyclin D1 serves as a cell regulatory switch in actively proliferating cells. Curr Opin Cell Biol 15(2):158–163

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Alao JP (2007) The regulation of Cyclin D1 degradation; role in cancer development and potential for therapeutic intervention. Mol Cancer 6:24

    Article  PubMed  Google Scholar 

  30. 30.

    Hui R, Finnay GL, Carroll JS, Lee CS, Mugrove EA, Sutherland RL (2002) Constitutive overexpression of Cyclin D1 but not Cyclin E confers acute resistance to anti estrogens in T-47 D breast cancer cells. Cancer Res 62(23):6916–6923

    CAS  PubMed  Google Scholar 

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This study was supported by a senior research fellowship from CSIR to Mayank Singh and by grant from DBT, Govt of India.

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Correspondence to Neeta Singh.

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Singh, M., Singh, N. Curcumin counteracts the proliferative effect of estradiol and induces apoptosis in cervical cancer cells. Mol Cell Biochem 347, 1–11 (2011).

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  • Cervical cancer
  • Estradiol
  • Curcumin
  • Telomerase
  • HPV