The anti-apoptotic role of interleukin-6 in human cervical cancer is mediated by up-regulation of Mcl-1 through a PI 3-K/Akt pathway

Oncogene. 2001 Sep 13;20(41):5799-809. doi: 10.1038/sj.onc.1204733.

Abstract

Interleukin-6 (IL-6), a multifunctional cytokine, has recently been implicated in human cervical cancer, though the mechanism remains elusive. This study demonstrates that the anti-apoptotic protein Mcl-1 and IL-6 was concomitantly expressed in human cervical cancer tissues and cell lines, but not in normal cervix tissues. Upon IL-6 treatment, Mcl-1, but not other Bcl-2 family members, was rapidly up-regulated peaking at 4-8 h in human cervical cancer C33A cells. Supporting this observation, using anti-IL-6 or anti-IL-6 receptor antibody to interrupt the IL-6 autocrine loop in SiHa cells significantly reduced cellular level of Mcl-1. This study hypothesizes that the expression of Mcl-1 in cervical cancer cells is regulated by IL-6. The matter of which signaling pathways transduced by IL-6 is responsible for the Mcl-1 up-regulation is further investigated herein. Blocking the STAT3 or MAPK pathway with dominant-negative mutant STAT3F or the MEK inhibitor PD98059 failed to inhibit IL-6-mediated Mcl-1 expression. Meanwhile, the IL-6-induced Mcl-1 up-regulation was effectively abolished by treatment with PI 3-K inhibitors, LY294002. Additionally, overexpression of dominant-negative (dn) Akt in C33A cells could inhibit the IL-6-induced increase of Mcl-1. Finally, overexpression of IL-6 in C33A cells caused a markable resistance to apoptosis induced by doxorubicin or cisplatin. Transient transfection of IL-6-overexpressed cells with a mcl-1 antisense vector, leading to the attenuation of their apoptosis-resistant activity. In conclusion, the data herein suggest that IL-6 regulated the mcl-1 expression via a PI 3-K/Akt-dependent pathway that may facilitate the oncogenesis of human cervical cancer by modulating the apoptosis threshold.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / physiopathology*
  • Doxorubicin / pharmacology
  • Female
  • Green Fluorescent Proteins
  • HeLa Cells
  • Humans
  • Interleukin-6 / metabolism
  • Interleukin-6 / physiology*
  • Luminescent Proteins / metabolism
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins / metabolism*
  • Neoplasm Proteins / physiology*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Proto-Oncogene Proteins*
  • Signal Transduction
  • Transfection
  • Tumor Cells, Cultured / drug effects
  • Up-Regulation
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / physiopathology*

Substances

  • Antineoplastic Agents
  • Interleukin-6
  • Luminescent Proteins
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Neoplasm Proteins
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Green Fluorescent Proteins
  • Doxorubicin
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt