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Modulation of insulin/IGFs pathways by sirtuin-7 inhibition in drug-induced chemoreistance

Ahmad Aljada1, Ayman M Saleh, Salem Al Suwaidan

  • 1Department of Basic Medical Sciences, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, P, O, Box 22490, Riyadh 11426, Kingdom of Saudi Arabia. aljadaa@ksau-hs.edu.sa.

Diagnostic Pathology
|June 3, 2014
PubMed
Abstract

Insights

Stress-induced Sirtuin-7 (Sirt7) inhibition enhances cancer cell resistance and alters insulin/IGF-1 signaling. This study links Sirt7 to drug-induced stress resistance in neoplasia.

Area of Science:

  • Molecular biology
  • Cancer research
  • Endocrinology

Background:

  • Insulin and insulin-like growth factors (IGFs) are crucial for metabolism and growth.
  • Their role in neoplasia and the underlying metabolic pathways are not fully understood.

Purpose of the Study:

  • Investigate insulin/IGF pathways in drug-sensitive and resistant cancer cells (MCF-7, SaOS-2, A2780).
  • Examine the impact of Sirtuin-7 (Sirt7) inhibition on these pathways in MCF-7 cells.

Main Methods:

  • Generated drug-resistant cell lines via prolonged exposure to Doxorubicin or Cisplatin.
  • Utilized siRNA to inhibit Sirt7 in MCF-7 cells.
  • Measured gene expression (Sirt7, INSR, IRS-1/2/4, IGF-1/2, MDR-1, MRP-1, BCRP) via qPCR and Western blotting.
  • Assessed insulin uptake using confocal microscopy.

Main Results:

  • Drug resistance led to inhibited insulin receptor (INSR) and insulin receptor substrate-1 (IRS-1), but induced IRS-2.
  • Insulin-like growth factors (IGF-1, IGF-2) were upregulated in resistant cells.
  • Sirt7 expression decreased in chemoresistant cells; Sirt7 knockdown induced senescence and multi-drug resistance.
  • Sirt7 suppression inhibited INSR, IRS-1, and insulin uptake, while upregulating IGF-1, IGF-2, and IGFR.

Conclusions:

  • Stress-induced Sirt7 inhibition increases cancer cell resistance and modulates insulin/IGF-1 signaling.
  • This study establishes a link between Sir2 family proteins and insulin/IGF signaling in drug-induced stress resistance in cancer.

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