Molecular and Cellular Biochemistry

, Volume 448, Issue 1–2, pp 311–320 | Cite as

AKIP1 promotes angiogenesis and tumor growth by upregulating CXC-chemokines in cervical cancer cells

  • Wenying Zhang
  • Qiongwei Wu
  • Chao Wang
  • Longtao Yang
  • Ping Liu
  • Chengbin Ma


Upregulation of A-kinase-interacting protein 1 (AKIP1) has been observed in breast and esophageal cancers, indicating that AKIP1 may be a potent oncogenic protein. However, the role of AKIP1 in cervical cancer still remains unknown. This study aimed to explore the role of AKIP1 in cervical cancer and to investigate the underlying mechanism of AKIP1 in tumor growth. Expression of AKIP1 in cervical cancer cells was determined by qRT-PCR and western blotting. Cell-Light EdU and colony formation assays were used to determine cell proliferation. CXCL1 and CXCL8 proteins were quantified by ELISA kits. Western blotting and qRT-PCR were used to examine the alterations in signaling-related proteins and mRNA, respectively. Endothelial cell tube formation assay was performed to evaluate the effect of AKIP1 on angiogenesis. A BALB/c nude mouse xenograft model was used to evaluate the role of AKIP1 in vivo. Cancer cell proliferation was inhibited and tumor growth and angiogenesis restrained in BALB/c nude mice by suppressing AKIP1 expression in cervical cancer cell lines. In addition, overexpression of AKIP1 in cervical cancer cells elevated the levels of CXCL1, CXCL2, and CXCL8. These three chemokines were not only involved in endothelial tube formation by binding to the endothelial receptor CXCR2, but also in cervical cancer cell proliferation and clone formation, which were induced by overexpression of AKIP1. Furthermore, we found that AKIP1-induced chemokine expression was decreased by an inhibitor of nuclear factor kappa-B kinase subunit β. These results show that AKIP1 is crucial in cervical cancer angiogenesis and growth by elevating the levels of the NF-κB-dependent chemokines CXCL1, CXCL2, and CXCL8.


AKIP1 Cervical cancer Angiogenesis Chemokines IKKβ 



This study was supported by a Fund Project of the Changning District Science and Technology Commission (CNKW2015Y16).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interests.


  1. 1.
    Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62(1):10–29. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Bosch FX, de Sanjose S (2007) The epidemiology of human papillomavirus infection and cervical cancer. Dis Mark 23(4):213–227CrossRefGoogle Scholar
  3. 3.
    Barakat RR, Markman M, Randall M (2009) Principles and practice of gynecologic oncology. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  4. 4.
    Bremnes RM, Camps C, Sirera R (2006) Angiogenesis in non-small cell lung cancer: the prognostic impact of neoangiogenesis and the cytokines VEGF and bFGF in tumours and blood. Lung Cancer 51(2):143–158. CrossRefPubMedGoogle Scholar
  5. 5.
    Scotton CJ, Wilson JL, Milliken D, Stamp G, Balkwill FR (2001) Epithelial cancer cell migration: a role for chemokine receptors? Cancer Res 61(13):4961–4965PubMedGoogle Scholar
  6. 6.
    Kitching R, Li H, Wong MJ, Kanaganayakam S, Kahn H, Seth A (2003) Characterization of a novel human breast cancer associated gene (BCA3) encoding an alternatively spliced proline-rich protein. Biochim Biophys Acta 1625(1):116–121CrossRefGoogle Scholar
  7. 7.
    Sastri M, Barraclough DM, Carmichael PT, Taylor SS (2005) A-kinase-interacting protein localizes protein kinase A in the nucleus. Proc Natl Acad Sci USA 102(2):349–354. CrossRefPubMedGoogle Scholar
  8. 8.
    Sastri M, Haushalter KJ, Panneerselvam M, Chang P, Fridolfsson H, Finley JC, Ng D, Schilling JM, Miyanohara A, Day ME, Hakozaki H, Petrosyan S, Koller A, King CC, Darshi M, Blumenthal DK, Ali SS, Roth DM, Patel HH, Taylor SS (2013) A kinase interacting protein (AKIP1) is a key regulator of cardiac stress. Proc Natl Acad Sci USA 110(5):E387–E396. CrossRefGoogle Scholar
  9. 9.
    Benedetti Panici P, Basile S, Angioli R (2009) Pelvic and aortic lymphadenectomy in cervical cancer: the standardization of surgical procedure and its clinical impact. Gynecol Oncol 113(2):284–290. CrossRefPubMedGoogle Scholar
  10. 10.
    Gao N, Hibi Y, Cueno M, Asamitsu K, Okamoto T (2010) A-kinase-interacting protein 1 (AKIP1) acts as a molecular determinant of PKA in NF-kappaB signaling. J Biol Chem 285(36):28097–28104. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Schmitt J, Matei D (2012) Targeting angiogenesis in ovarian cancer. Cancer Treat Rev 38(4):272–283. CrossRefPubMedGoogle Scholar
  12. 12.
    Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim J, Morris PG, Manova-Todorova K, Leversha M, Hogg N, Seshan VE, Norton L, Brogi E, Massague J (2012) A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150(1):165–178. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Bolitho C, Hahn MA, Baxter RC, Marsh DJ (2010) The chemokine CXCL1 induces proliferation in epithelial ovarian cancer cells by transactivation of the epidermal growth factor receptor. Endocr Relat Cancer 17(4):929–940. CrossRefPubMedGoogle Scholar
  14. 14.
    Merritt WM, Lin YG, Spannuth WA, Fletcher MS, Kamat AA, Han LY, Landen CN, Jennings N, De Geest K, Langley RR, Villares G, Sanguino A, Lutgendorf SK, Lopez-Berestein G, Bar-Eli MM, Sood AK (2008) Effect of interleukin-8 gene silencing with liposome-encapsulated small interfering RNA on ovarian cancer cell growth. J Natl Cancer Inst 100(5):359–372. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Yang G, Rosen DG, Zhang Z, Bast RC Jr, Mills GB, Colacino JA, Mercado-Uribe I, Liu J (2006) The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc Natl Acad Sci USA 103(44):16472–16477. CrossRefPubMedGoogle Scholar
  16. 16.
    Willmott LJ, Monk BJ (2009) Cervical cancer therapy: current, future and anti-angiogensis targeted treatment. Expert Rev Anticancer Ther 9(7):895–903. CrossRefPubMedGoogle Scholar
  17. 17.
    Mo D, Li X, Li C, Liang J, Zeng T, Su N, Jiang Q, Huang J (2016) Overexpression of AKIP1 predicts poor prognosis of patients with breast carcinoma and promotes cancer metastasis through Akt/GSK-3beta/Snail pathway. Am J Transl Res 8(11):4951–4959PubMedPubMedCentralGoogle Scholar
  18. 18.
    Yu H, Tigchelaar W, Koonen DP, Patel HH, de Boer RA, van Gilst WH, Westenbrink BD, Sillje HH (2013) AKIP1 expression modulates mitochondrial function in rat neonatal cardiomyocytes. PLoS ONE 8(11):e80815. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Yancopoulos GD, Davis S, Gale NW, Rudge JS, Wiegand SJ, Holash J (2000) Vascular-specific growth factors and blood vessel formation. Nature 407(6801):242–248. CrossRefGoogle Scholar
  20. 20.
    Bergers G, Benjamin LE (2003) Tumorigenesis and the angiogenic switch. Nat Rev Cancer 3(6):401–410. CrossRefPubMedGoogle Scholar
  21. 21.
    Randall LM, Monk BJ, Darcy KM, Tian C, Burger RA, Liao SY, Peters WA, Stock RJ, Fruehauf JP (2009) Markers of angiogenesis in high-risk, early-stage cervical cancer: a gynecologic oncology group study. Gynecol Oncol 112(3):583–589. CrossRefPubMedGoogle Scholar
  22. 22.
    Kodama J, Seki N, Tokumo K, Hongo A, Miyagi Y, Yoshinouchi M, Okuda H, Kudo T (1999) Vascular endothelial growth factor is implicated in early invasion in cervical cancer. Eur J Cancer 35(3):485–489CrossRefGoogle Scholar
  23. 23.
    Pietras K, Pahler J, Bergers G, Hanahan D (2008) Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Med 5(1):e19. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8(8):618–631. CrossRefPubMedGoogle Scholar
  25. 25.
    Flanagan K, Kaufman HL (2002) Chemokines and cancer. Cancer Invest 20(5–6):825–834CrossRefGoogle Scholar
  26. 26.
    Kodama J, Kusumoto T, Seki N, Matsuo T, Ojima Y, Nakamura K, Hongo A, Hiramatsu Y (2007) Association of CXCR4 and CCR7 chemokine receptor expression and lymph node metastasis in human cervical cancer. Ann Oncol 18(1):70–76. CrossRefPubMedGoogle Scholar
  27. 27.
    Balkwill F (2004) Cancer and the chemokine network. Nat Rev Cancer 4(7):540–550. CrossRefPubMedGoogle Scholar
  28. 28.
    Wang Y, Xu RC, Zhang XL, Niu XL, Qu Y, Li LZ, Meng XY (2012) Interleukin-8 secretion by ovarian cancer cells increases anchorage-independent growth, proliferation, angiogenic potential, adhesion and invasion. Cytokine 59(1):145–155. CrossRefPubMedGoogle Scholar
  29. 29.
    Hayden MS, Ghosh S (2008) Shared principles in NF-kappaB signaling. Cell 132(3):344–362. CrossRefPubMedGoogle Scholar
  30. 30.
    Duckworth C, Zhang L, Carroll SL, Ethier SP, Cheung HW (2016) Overexpression of GAB2 in ovarian cancer cells promotes tumor growth and angiogenesis by upregulating chemokine expression. Oncogene 35(31):4036–4047. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Wenying Zhang
    • 1
  • Qiongwei Wu
    • 1
  • Chao Wang
    • 1
  • Longtao Yang
    • 1
  • Ping Liu
    • 1
  • Chengbin Ma
    • 1
  1. 1.Gynecology DepartmentChangning Maternity and Infant Health HospitalShanghaiChina

Personalised recommendations