Inhibition of p38 mitogen-activated protein kinase alters microRNA expression and reverses epithelial-to-mesenchymal transition

James W. Antoon, Ashley M. Nitzchke, Elizabeth C. Martin, Lyndsay V. Rhodes, Seungyoon Nam, Scott Wadsworth, Virgilo A. Salvo, Steven Elliott, Bridgette Collins-Burow, Kenneth Nephew, Matthew E. Burow

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Acquired chemoresistance and epithelial-to-mesenchymal transition (EMT) are hallmarks of cancer progression and of increasing clinical relevance. We investigated the role of miRNA and p38 mitogen-activated protein kinase (MAPK) signaling in the progression of breast cancer to a drug-resistant and mesenchymal phenotype. We demonstrate that acquired death receptor resistance results in increased hormone-independent tumorigenesis compared to hormone-sensitive parental cells. Utilizing global miRNA gene expression profiling, we identified miRNA alterations associated with the development of death receptor resistance and EMT progression. We further investigated the role of p38 MAPK in this process, showing dose-dependent inactivation of p38 by its inhibitor RWJ67657 and decreased downstream ATF and NF-.B signaling. Pharmacological inhibition of p38 also decreased chemoresistant cancer tumor growth in xenograft animal models. Interestingly, inhibition of p38 partially reversed the EMT changes found in this cell system, as illustrated by decreased gene expression of the EMT markers Twist, Snail, Slug and ZEB and protein and mRNA levels of Twist, a known EMT promoter, concomitant with decreased N-cadherin protein. RWJ67657 treatment also altered the expression of several miRNAs known to promote therapeutic resistance, including miR-200, miR-303, miR-302, miR-199 and miR-328. Taken together, our results demonstrate the roles of multiple microRNAs and p38 signaling in the progression of cancer and demonstrate the therapeutic potential of targeting the p38 MAPK pathway for reversing EMT in an advanced tumor phenotype.

Original languageEnglish
Pages (from-to)1139-1150
Number of pages12
JournalInternational Journal of Oncology
Volume42
Issue number4
DOIs
StatePublished - Apr 2013

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Epithelial-Mesenchymal Transition
p38 Mitogen-Activated Protein Kinases
MicroRNAs
Death Domain Receptors
Neoplasms
Hormones
Phenotype
Gastropoda
Gene Expression Profiling
Cadherins
Heterografts
Carcinogenesis
Proteins
Animal Models
Pharmacology
Breast Neoplasms
Gene Expression
Messenger RNA
Therapeutics
Growth

Keywords

  • Breast cancer
  • Drug discovery
  • Epithelial-to-mesenchymal transition
  • P38 mitogen-activated protein kinase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Antoon, J. W., Nitzchke, A. M., Martin, E. C., Rhodes, L. V., Nam, S., Wadsworth, S., ... Burow, M. E. (2013). Inhibition of p38 mitogen-activated protein kinase alters microRNA expression and reverses epithelial-to-mesenchymal transition. International Journal of Oncology, 42(4), 1139-1150. https://doi.org/10.3892/ijo.2013.1814

Inhibition of p38 mitogen-activated protein kinase alters microRNA expression and reverses epithelial-to-mesenchymal transition. / Antoon, James W.; Nitzchke, Ashley M.; Martin, Elizabeth C.; Rhodes, Lyndsay V.; Nam, Seungyoon; Wadsworth, Scott; Salvo, Virgilo A.; Elliott, Steven; Collins-Burow, Bridgette; Nephew, Kenneth; Burow, Matthew E.

In: International Journal of Oncology, Vol. 42, No. 4, 04.2013, p. 1139-1150.

Research output: Contribution to journalArticle

Antoon, JW, Nitzchke, AM, Martin, EC, Rhodes, LV, Nam, S, Wadsworth, S, Salvo, VA, Elliott, S, Collins-Burow, B, Nephew, K & Burow, ME 2013, 'Inhibition of p38 mitogen-activated protein kinase alters microRNA expression and reverses epithelial-to-mesenchymal transition', International Journal of Oncology, vol. 42, no. 4, pp. 1139-1150. https://doi.org/10.3892/ijo.2013.1814
Antoon, James W. ; Nitzchke, Ashley M. ; Martin, Elizabeth C. ; Rhodes, Lyndsay V. ; Nam, Seungyoon ; Wadsworth, Scott ; Salvo, Virgilo A. ; Elliott, Steven ; Collins-Burow, Bridgette ; Nephew, Kenneth ; Burow, Matthew E. / Inhibition of p38 mitogen-activated protein kinase alters microRNA expression and reverses epithelial-to-mesenchymal transition. In: International Journal of Oncology. 2013 ; Vol. 42, No. 4. pp. 1139-1150.
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