# Spatial sequestration of activated-caspase 3 in aggresomes mediates resistance of neuroblastoma cell to bortezomib treatment

## TL;DR

This study reveals a new mechanism of resistance to bortezomib in neuroblastoma cells involving the sequestration of active caspase 3 in aggresomes.

## Contribution

The study identifies a novel resistance mechanism involving spatial sequestration of activated caspase 3 in aggresomes.

## Key findings

- Activated caspase 3 accumulates in aggresomes of resistant neuroblastoma cells.
- This sequestration impairs apoptosis and increases cell survival during bortezomib treatment.
- The mechanism may explain resistance in patients and suggests targeting aggresomes as a potential therapy.

## Abstract

Neuroblastoma (NB) is the most common pediatric tumor and is currently treated by several types of therapies including chemotherapies, such as bortezomib treatment. However, resistance to bortezomib is frequently observed by mechanisms that remain to be deciphered. Bortezomib treatment leads to caspase activation and aggresome formation. Using models of patients-derived NB cell lines with different levels of sensitivity to bortezomib, we show that the activated form of caspase 3 accumulates within aggresomes of NB resistant cells leading to an impairment of bortezomib-induced apoptosis and increased cell survival. Our findings unveil a new mechanism of resistance to chemotherapy based on an altered subcellular distribution of the executioner caspase 3. This mechanism could explain the resistance developed in NB patients treated with bortezomib, emphasizing the potential of drugs targeting aggresomes.