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Ras inhibits endoplasmic reticulum stress in human cancer cells with amplified Myc

Shira Yaari-Stark1, Maayan Shaked, Yael Nevo-Caspi

  • 1Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel.

International Journal of Cancer
|December 10, 2009
PubMed

Insights

Ras inhibition halts growth in Myc-amplified cancer cells by inducing endoplasmic reticulum (ER) stress. This Ras-mediated protection against ER stress is crucial for Myc-amplified cells, revealing a new therapeutic vulnerability.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Stress Response

Background:

  • Amplification of the Myc gene is common in aggressive cancers, often cooperating with active Ras signaling.
  • Ras inhibitors like farnesylthiosalicylic acid (FTS) have shown potential in disrupting Ras-Myc cooperation and arresting cancer cell growth.
  • The generalizability of FTS effects across different Myc-amplified cancer types requires further investigation.

Purpose of the Study:

  • To determine if the growth arrest and cell death induced by FTS in Myc-amplified neuroblastoma cells is a general phenomenon in other Myc-amplified cancer cell lines.
  • To elucidate the molecular mechanisms underlying FTS-induced cell death in Myc-amplified cells, particularly focusing on endoplasmic reticulum (ER) stress pathways.
  • To investigate the role of Ras in regulating ER stress in the context of Myc amplification.

Main Methods:

  • Treatment of various cancer cell lines (NCIH929 myeloma, K562 leukemia, LAN-1 neuroblastoma, SHEP neuroblastoma) with FTS.
  • Gene-expression profiling to analyze cellular responses to FTS.
  • Induction of ER stress using dominant-negative Ras (DN-Ras) or small hairpin RNA (shRNA) targeting Ras isoforms.
  • Analysis of key ER stress markers including BIP, p-PERK, Nrf2, eIF2alpha, ATF4, and ATF3.
  • Inhibition of MAPK pathway components (p38, MEK) and PERK to assess their role in FTS-induced effects.

Main Results:

  • FTS induced cell growth arrest and death in Myc-amplified cell lines (LAN-1, NCIH929, K562) but not in the non-amplified SHEP cells.
  • A common pattern of FTS-induced endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) was observed in Myc-amplified cells.
  • Ras was found to negatively regulate ER stress in Myc-amplified cells, with Ras inhibition leading to increased ER stress markers.
  • The Ras-MAPK pathway (p38, MEK) was identified as a key regulator negatively controlling ER stress cascades (BIP/PERK/Nrf2 and eIF2alpha/ATF4/ATF3).

Conclusions:

  • Ras negatively regulates ER stress in cells with amplified Myc, providing a protective mechanism against ER stress-associated death.
  • FTS effectively induces ER stress and cell death in Myc-amplified cancer cells, highlighting a potential therapeutic strategy.
  • Targeting the Ras-MAPK-ER stress axis presents a promising avenue for cancer therapy, particularly in tumors with Myc amplification.

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