Cycling quiescence in temozolomide resistant glioblastoma cells is partly explained by microRNA-93 and -193-mediated decrease of cyclin D

Jessian L. Munoz, Nykia D. Walker, Satvik Mareedu, Sri Harika Pamarthi, Garima Sinha, Steven J. Greco, Pranela Rameshwar

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Glioblastoma multiforme (GBM) is a fatal malignancy of the central nervous system, commonly associated with chemoresistance. The alkylating agent Temozolomide (TMZ) is the front-line chemotherapeutic agent and has undergone intense studies on resistance. These studies reported on mismatch repair gene upregulation, ABC-targeted drug efflux, and cell cycle alterations. The mechanism by which TMZ induces cell cycle arrest has not been well-established. TMZ-resistant GBM cells have been linked to microRNA (miRNA) and exosomes. A cell cycle miRNA array identified distinct miRNAs only in exosomes from TMZ-resistant GBM cell lines and primary spheres. We narrowed the miRs to miR-93 and -193 and showed in computational analyses that they could target Cyclin D1. Since Cyclin D1 is a major regulator of cell cycle progression, we performed cause-effect studies and showed a blunting effects of miR-93 and -193 in Cyclin D1 expression. These two miRs also decreased cell cycling quiescence and induced resistance to TMZ. Taken together, our data provide a mechanism by which GBM cells can exhibit TMZ-induced resistance through miRNA targeting of Cyclin D1. The data provide a number of therapeutic approaches to reverse chemoresistance at the miRNA, exosomal and cell cycle points.

Original languageEnglish (US)
Article number134
JournalFrontiers in Pharmacology
Volume10
Issue numberFEB
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Keywords

  • Cell cycle
  • Chemoresistance
  • Cyclin D
  • Glioblastoma
  • MicroRNA

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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