Related Experiment Video

Updated: May 4, 2026

Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells
08:47

Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells

Published on: May 1, 2020

2.5K

Adaptation to mTOR kinase inhibitors by amplification of eIF4E to maintain cap-dependent translation

Claire L Cope1, Rebecca Gilley, Kathryn Balmanno

  • 1Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.

Journal of Cell Science
|December 24, 2013
PubMed

Insights

Acquired resistance to mTOR inhibitors in colon cancer cells involves increased eIF4E, promoting cap-dependent translation and blocking drug efficacy. This highlights eIF4E

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • The mechanistic target of rapamycin (mTOR) kinase is a crucial regulator of cell growth and a target in cancer therapy.
  • Understanding cellular adaptation to chronic mTOR inhibition is vital for developing effective anti-cancer strategies.
  • mTOR signaling pathways, including mTORC1 and mTORC2, control protein synthesis and cell proliferation.

Purpose of the Study:

  • To investigate the mechanisms of acquired resistance to mTOR kinase inhibitors in colon cancer cells.
  • To identify key molecular players and signaling pathways involved in resistance to AZD8055.
  • To evaluate the therapeutic implications of mTOR inhibitor resistance for combination therapies.

Main Methods:

  • Generation of AZD8055-resistant SW620 colon cancer cells (SW620:8055R).
  • Analysis of mTORC1/mTORC2 signaling, translation initiation factors (eIF4E), and mRNA translation modes (cap-dependent vs. IRES).
  • RNA interference (RNAi)-mediated knockdown of eIF4E and assessment of drug sensitivity; use of a heterologous cell system to test eIF4E overexpression effects.

Main Results:

  • SW620:8055R cells showed loss of S6K signaling and increased eIF4E expression, leading to enhanced cap-dependent translation.
  • Expression of CCND1 and MCL1, regulated by eIF4E, became refractory to AZD8055 in resistant cells.
  • Knockdown of eIF4E restored sensitivity to AZD8055, while eIF4E overexpression reduced sensitivity.
  • Resistant cells exhibited cross-resistance to MEK1/2 inhibitor selumetinib, indicating pathway convergence.

Conclusions:

  • Acquired resistance to mTOR inhibitors is mediated by increased eIF4E, which promotes cap-dependent translation and cell proliferation.
  • The convergence of ERK1/2 and mTOR signaling at eIF4E is a critical mechanism underlying resistance.
  • Therapeutic strategies targeting mTOR and MEK1/2 pathways need to consider the role of eIF4E in resistance and cross-resistance.
Keywords:
4EBP1Cell proliferationDrug resistanceGene amplificationeIF4EmTOR

More Related Videos

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

951
Xenopus laevis as a Model to Identify Translation Impairment10:24

Xenopus laevis as a Model to Identify Translation Impairment

Published on: September 27, 2015

10.3K

Related Concept Videos

mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.6K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

1.5K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
5.1K
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
7.3K
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.3K
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
15.3K