Everolimus sensitizes Ras-transformed cells to radiation in vitro through the autophagy pathway

Int J Mol Med. 2014 Nov;34(5):1417-22. doi: 10.3892/ijmm.2014.1927. Epub 2014 Sep 9.

Abstract

Modern radiation therapy strives to minimize injury to organs while increasing the anticancer effects. The present study aimed to investigate the radiosensitizing effects of everolimus and to examine the molecular mechanisms responsible for everolimus‑mediated radiosensitization. Radiation in combination with everolimus (30 nM) sensitized Ras-transformed cells to radiation in vitro. Radiation induced apoptotic markers (sub-G1 cell accumulation, membrane inversion and DNA fragmentation) and treatment with everolimus did not promote radiation-induced apoptosis. However, LC3-II expression increased following combination treatment with everolimus and radiation, and the radiosensitizing effects of everolimus were reversed following transfection with small interfering RNA (siRNA) targeting Beclin 1. In addition, the protein levels of activated S6 kinase 1 (S6K1) were significantly reduced following treatment with everolimus, and the phosphorylation of factor 4E binding protein 1 (4EBP1) was suppressed following combination treatment. Taken together, our data demonstrate that everolimus sensitizes Ras-transformed cells to radiation in vitro. Everolimus-mediated radiosensitization is associated with the autophagy pathway. Thus, everolimus is a novel radiosensitizing agent with potential for use in cancer radiotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagy / drug effects*
  • Autophagy / radiation effects*
  • Beclin-1
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Cycle / radiation effects
  • Cell Line
  • DNA Fragmentation / drug effects
  • DNA Fragmentation / radiation effects
  • Everolimus
  • In Situ Nick-End Labeling
  • Intracellular Signaling Peptides and Proteins
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphorylation
  • RNA, Small Interfering / genetics
  • Radiation
  • Radiation-Sensitizing Agents / pharmacology*
  • Radiotherapy / methods
  • Rats
  • Ribosomal Protein S6 Kinases / genetics
  • Ribosomal Protein S6 Kinases / metabolism
  • Sirolimus / analogs & derivatives*
  • Sirolimus / pharmacology
  • Transfection

Substances

  • Apoptosis Regulatory Proteins
  • Beclin-1
  • Becn1 protein, rat
  • Carrier Proteins
  • Eif4ebp1 protein, rat
  • Intracellular Signaling Peptides and Proteins
  • LC3 protein, rat
  • Microtubule-Associated Proteins
  • Phosphoproteins
  • RNA, Small Interfering
  • Radiation-Sensitizing Agents
  • Everolimus
  • Ribosomal Protein S6 Kinases
  • Rps6kb1 protein, rat
  • Sirolimus