Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231

Anna De Blasio, Riccardo Di Fiore, Marco Morreale, Daniela Carlisi, Rosa Drago-Ferrante, Mauro Montalbano, Christian Scerri, Giovanni Tesoriere, Renza Vento

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Triple-negative breast cancer (TNBC) is a clinically aggressive form of breast cancer that is unresponsive to endocrine agents or trastuzumab. TNBC accounts for ∼10-20% of all breast cancer cases and represents the form with the poorest prognosis. Patients with TNBC are at higher risk of early recurrence, mainly in the lungs, brain and soft tissue, therefore, there is an urgent need for new therapies. The present study was carried out in MDA-MB-231 cells, where we assessed the role of caspase-8 (casp-8), a critical effector of death receptors, also involved in non-apoptotic functions. Analysis of casp-8 mRNA and protein levels indicated that they were up-regulated with respect to the normal human mammalian epithelial cells. We demonstrated that silencing of casp-8 by small interfering-RNA, strongly decreased MDA-MB-231 cell growth by delaying G0/G1-to S-phase transition and increasing p21, p27 and hypo-phosphorylated/active form of pRb levels. Surprisingly, casp-8-knockdown, also potently increased both the migratory and metastatic capacity of MDA-MB-231 cells, as shown by both wound healing and Matrigel assay, and by the expression of a number of related-genes and/or proteins such as VEGFA, C-MYC, CTNNB1, HMGA2, CXCR4, KLF4, VERSICAN V1 and MMP2. Among these, KLF4, a transcriptional factor with a dual role (activator and repressor), seemed to play critical roles. We suggest that in MDA-MB-231 cells, the endogenous expression of casp-8 might keep the cells perpetually cycling through downregulation of KLF4, the subsequent lowering of p21 and p27, and the inactivation by hyperphosphorylation of pRb. Simultaneously, by lowering the expression of some migratory and invasive genes, casp-8 might restrain the metastatic ability of the cells. Overall, our findings showed that, in MDA-MB-231 cells, casp-8 might play some unusual roles which should be better explored, in order to understand whether it might be identified as a molecular therapeutic target.

Original languageEnglish (US)
Pages (from-to)2339-2348
Number of pages10
JournalInternational Journal of Oncology
Volume48
Issue number6
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Fingerprint

Triple Negative Breast Neoplasms
Caspase 8
Cell Line
Versicans
Breast Neoplasms
Death Domain Receptors
Phase Transition
S Phase
Wound Healing
Small Interfering RNA
Proteins
Down-Regulation
Epithelial Cells
Recurrence
Lung
Messenger RNA
Brain
Therapeutics
Growth

Keywords

  • Caspase-8 knockdown
  • Caspase-8 unusual roles
  • Cell cycle regulators
  • Invasivity and metastasis
  • KLF4
  • MDA-MB-231 cells
  • Triple-negative breast cancer cells

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

De Blasio, A., Di Fiore, R., Morreale, M., Carlisi, D., Drago-Ferrante, R., Montalbano, M., ... Vento, R. (2016). Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231. International Journal of Oncology, 48(6), 2339-2348. https://doi.org/10.3892/ijo.2016.3474

Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231. / De Blasio, Anna; Di Fiore, Riccardo; Morreale, Marco; Carlisi, Daniela; Drago-Ferrante, Rosa; Montalbano, Mauro; Scerri, Christian; Tesoriere, Giovanni; Vento, Renza.

In: International Journal of Oncology, Vol. 48, No. 6, 01.01.2016, p. 2339-2348.

Research output: Contribution to journalArticle

De Blasio, A, Di Fiore, R, Morreale, M, Carlisi, D, Drago-Ferrante, R, Montalbano, M, Scerri, C, Tesoriere, G & Vento, R 2016, 'Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231', International Journal of Oncology, vol. 48, no. 6, pp. 2339-2348. https://doi.org/10.3892/ijo.2016.3474
De Blasio, Anna ; Di Fiore, Riccardo ; Morreale, Marco ; Carlisi, Daniela ; Drago-Ferrante, Rosa ; Montalbano, Mauro ; Scerri, Christian ; Tesoriere, Giovanni ; Vento, Renza. / Unusual roles of caspase-8 in triple-negative breast cancer cell line MDA-MB-231. In: International Journal of Oncology. 2016 ; Vol. 48, No. 6. pp. 2339-2348.
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