# In long-lasting cellular stress phases of melanoma cells, stress granules are dissolved by HSP70

## TL;DR

Melanoma cells survive stress by using HSP70 instead of stress granules, making them resistant to treatments like Vemurafenib.

## Contribution

Identifies HSP70 as a key stress resistance mechanism in melanoma cells, bypassing the need for stress granules.

## Key findings

- High HSP70 levels in melanoma cells preserve protein homeostasis and inhibit apoptosis under stress.
- Silencing HSP70 increases stress granule formation and sensitizes melanoma cells to Vemurafenib.
- HSP70 compensates for stress granules, promoting resistance to therapeutic stress in melanoma.

## Abstract

Cancer cells must adapt to harsh microenvironmental conditions such as nutrient deprivation, hypoxia and immune pressure to sustain their high proliferative potential. One adaptive mechanism involves the formation of stress granules (SGs), which promote cell survival under stress. Interestingly, melanoma cells appear to tolerate such stressors, including hypoxia and chemotherapeutic agents, with minimal dependence on SG formation. In this study, we identify heat shock protein 70 (HSP70) as a key mediator of stress resistance in melanoma cells and the participation of the kinase CK2 in this process. We demonstrate that melanoma cells express high endogenous levels of HSP70, which preserves protein homeostasis and inhibits apoptosis under both environmental and drug-induced stress. Silencing of HSP70 led to increased SG formation and sensitized melanoma cells to apoptosis, particularly in response to the BRAF inhibitor Vemurafenib. These findings suggest that HSP70 plays a central role in melanoma cell survival by compensating for the need for SGs and promoting resistance to therapeutic stress.

The online version contains supplementary material available at 10.1007/s00018-025-05939-8.