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8-Chloroadenosine Sensitivity in Renal Cell Carcinoma Is Associated with AMPK Activation and mTOR Pathway Inhibition

Alper Y Kearney1, You-Hong Fan2, Uma Giri2

  • 1Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

Plos One
|August 28, 2015
PubMed

Insights

The cancer drug 8-chloroadenosine inhibits clear cell renal cell carcinoma (ccRCC) growth by impacting the mTOR pathway. Its effectiveness is linked to AMPK activation and PI3K pathway status, suggesting potential for ccRCC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • 8-chloroadenosine depletes ATP and inhibits tumor growth in various cancers.
  • Clear cell renal cell carcinoma (ccRCC) is a significant solid tumor with limited targeted therapies.
  • The mTOR pathway is implicated in ccRCC pathogenesis and represents a potential therapeutic target.

Purpose of the Study:

  • To investigate the effects of 8-chloroadenosine on clear cell renal cell carcinoma (ccRCC) cell lines.
  • To elucidate the molecular mechanisms underlying 8-chloroadenosine's efficacy and resistance in ccRCC.
  • To explore the potential of 8-chloroadenosine as a therapeutic agent for ccRCC.

Main Methods:

  • In vitro assessment of ccRCC cell viability using 8-chloroadenosine.
  • Proteomic analysis via reverse-phase protein array to identify signaling pathway alterations.
  • Time-course experiments measuring protein phosphorylation (AMPK, ACC, p70S6K, RPS6, AKT).
  • Pharmacological inhibition of the PI3K pathway to assess synergistic effects.

Main Results:

  • 8-chloroadenosine demonstrated dose-dependent inhibition of ccRCC cell viability (IC50: 2–36 μM).
  • Treatment led to mTOR pathway inhibition, rapid AMPK activation, and subsequent dephosphorylation of p70S6K and RPS6 in sensitive cell lines.
  • Resistant cell lines showed unaffected AMPK and mTOR signaling, with elevated basal phospho RPS6 and AKT.
  • PI3K pathway inhibition enhanced 8-chloroadenosine efficacy across all tested cell lines.

Conclusions:

  • 8-chloroadenosine exerts its anti-cancer effects in ccRCC by inhibiting the mTOR pathway and activating AMPK.
  • Phospho RPS6 and PI3K pathway activation are potential determinants of resistance to 8-chloroadenosine.
  • Given ccRCC's susceptibility to mTOR inhibition, 8-chloroadenosine shows promise as a targeted therapy for this malignancy.

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