Breast Cancer Targeting through Inhibition of the Endoplasmic Reticulum-Based Apoptosis Regulator Nrh/BCL2L10

Adrien Nougarede1, Nikolay Popgeorgiev1, Loay Kassem2

  • 1Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Lyon, France.

Cancer Research
|January 14, 2018
PubMed

Insights

Targeting Nrh/BCL2L10, overexpressed in advanced breast cancers, offers a new strategy. Disrupting Nrh interactions with IP3R channels inhibits cancer cell growth, showing Nrh as a prognostic marker and therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Drug resistance and metastatic relapse are significant challenges in breast cancer treatment.
  • BCL-2 homolog Nrh/BCL2L10 (Nrh) is overexpressed in over 45% of invasive breast carcinomas.
  • Nrh overexpression correlates with reduced metastasis-free survival and is an independent poor prognostic marker.

Purpose of the Study:

  • To investigate the role of Nrh/BCL2L10 in advanced breast cancer.
  • To explore Nrh as a potential therapeutic target and prognostic marker.
  • To elucidate the mechanism of Nrh's antiapoptotic activity.

Main Methods:

  • Analysis of Nrh expression in a large cohort of breast invasive carcinomas.
  • Immunohistochemistry to determine Nrh protein localization.
  • Mechanistic studies involving interactions between Nrh and inositol-1,4,5-triphosphate receptor (IP3R).
  • In vitro and in vivo experiments using BH4 mimetic peptides to disrupt Nrh/IP3R complexes.

Main Results:

  • Nrh protein localizes to the endoplasmic reticulum.
  • Nrh interacts with IP3R (a Ca2+ channel) in a BH4 domain-dependent manner.
  • Nrh negatively regulates ER-Ca2+ release and mediates antiapoptosis.
  • Disruption of Nrh/IP3R complexes inhibits breast cancer cell growth both in vitro and in vivo.

Conclusions:

  • Nrh/BCL2L10 is a novel prognostic marker for breast cancer.
  • Nrh is a potential therapeutic target for advanced breast cancers.
  • Targeting Nrh/IP3R interactions offers a promising strategy for eradicating drug-resistant and metastatic breast cancers.

Related Concept Videos

Endoplasmic Reticulum01:39

Endoplasmic Reticulum

The Endoplasmic Reticulum (ER) in eukaryotic cells is a substantial network of interconnected membranes with diverse functions, from calcium storage to biomolecule synthesis. A primary component of the endomembrane system, the ER manufactures phospholipids critical for membrane function throughout the cell. Additionally, the two distinct regions of the ER specialize in the manufacture of specific lipids and proteins.
111.4K
The Endoplasmic Reticulum01:43

The Endoplasmic Reticulum

The endoplasmic reticulum or ER makes up for more than half of the membranes in a cell and accounts for 10% of total cell volume. It is also the primary protein and lipid synthesis factory for most cell organelles, such as the Golgi apparatus, lysosomes, secretory vesicles, and the plasma membrane. Despite being the most extensive and functionally complex subcellular organelle, ER was the last to be discovered. After years of deliberation, Keith Porter and George Palade in the year 1954,...
21.9K
Smooth Endoplasmic Reticulum01:21

Smooth Endoplasmic Reticulum

Smooth endoplasmic reticulum or smooth ER is a sub-organelle with specialized functions in animal cells and plant cells. It is often associated with the tubule morphology of the endoplasmic reticulum.
The ER provides optimal conditions for synthesizing steroid hormones and lipids, such as phospholipids and triglycerides. Traditionally, lipid metabolism was considered to be a smooth ER function. However, there is no direct evidence to prove that rough ER is completely excluded from lipid...
8.2K
Directing Proteins to the Rough Endoplasmic Reticulum01:34

Directing Proteins to the Rough Endoplasmic Reticulum

The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
17.9K
Regulated mRNA Transport02:22

Regulated mRNA Transport

In eukaryotes, transcription and translation are compartmentalized; an mRNA is first synthesized in the nucleus and then selectively transported to the cytoplasm for protein synthesis. Before transport, a pre-mRNA undergoes several steps of post-transcriptional modifications including splicing, 5' capping, and the addition of a poly-adenine tail. Various proteins bind to the pre-mRNA during these modifications. The mRNA transport takes place with the help of multiple proteins playing...
7.1K
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
38.6K