Interleukin-6 dependent induction of the cyclin dependent kinase inhibitor p21(WAF1/CIP1) is lost during progression of human malignant melanoma

Vivi Ann Flørenes, Chao Lu, Nandita Bhattacharya, Janusz Rak, Capucine Sheehan, Joyce M. Slingerland, Robert S. Kerbel

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Human melanoma cell lines derived from early stage primary tumors are particularly sensitive to growth arrest induced by interleukin-6 (IL-6). This response is lost in cell lines derived from advanced lesions, a phenomenon which may contribute to tumor aggressiveness. We sought to determine whether resistance to growth inhibition by IL-6 can be explained by oncogenic alterations in cell cycle regulators or relevant components of intracellular signaling. Our results show that IL-6 treatment of early stage melanoma cell lines caused G1 arrest, which could not be explained by changes in levels of G1 cyclins (D1, E), cdks (cdk4, cdk2) or by loss of cyclin/cdk complex formation. Instead, IL-6 caused a marked induction of the cdk inhibitor p21(WAF1/CIP1) in three different IL-6 sensitive cell lines, two of which also shelved a marked accumulation of the cdk inhibitor p27(Kip1). In contrast, IL-6 failed to induce p21(WAF1/CIP1) transcript and did not increase p21WAF1/CIP1 or p27(Kip1) proteins in any of the resistant lines. In fact, of five IL-6 resistant cell lines, only two expressed detectable levels of p21(WAF1/CIP1) mRNA and protein, while in three other lines, p21(WAF1/CIP1) was undetectable. IL-6 dependent upregulation of p21(WAF1/CIP1) was associated with binding of both STAT3 and STAT1 to the p21(WAF1/CIP1) promoter. Surprisingly, however, IL-6 stimulated STAT binding to this promoter in both sensitive and resistant cell lines (with one exception), suggesting that gross deregulation of this event is not the unifying cause of the defect in p21(WAF1/CIP1) induction in IL-6 resistant cells. In somatic cell hybrids of IL-6 sensitive and resistant cell lines, the resistant phenotype was dominant and IL-6 failed to induce p21(WAF1/CIP1). Thus, our results suggest that in early stage human melanoma cells, IL-6 induced growth inhibition involves induction of p21(WAF1/CIP1) which is lost in the course of tumor progression presumably as a result of a dominant oncogenic event.

Original languageEnglish (US)
Pages (from-to)1023-1032
Number of pages10
JournalOncogene
Volume18
Issue number4
DOIs
StatePublished - Jan 28 1999

Keywords

  • Melanoma, IL-6
  • p21(WAF1/CIP1)
  • p27(Kip1)
  • Sensitivity
  • STAT

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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