Inhibition of endoplasmic reticulum stress-induced autophagy sensitizes melanoma cells to temozolomide treatment.

Abstract:

:The incidence of malignant melanoma is increasing. The discovery of agents specifically targeting the mutated cascades has provided a good response for patients with oncogenic B-Raf proto-оncogene, serine/threonine kinase (BRAF). However, numerous studies continue to focus on novel methods of treatment to overcome acquired resistance to novel drugs. Recently, it has been revealed that inhibition of endoplasmic reticulum (ER) stress chaperon 78 kDa glucose-regulated protein 78 (GRP78) leads to down-regulation of autophagy and increased sensitivity to temozolomide (TMZ) treatment. Melanoma cells have a different sensitivity to TMZ treatment, which corresponds to the basal autophagy level. In the present study, we demonstrated that downregulation of GRP78 mitigated chemoresistance to TMZ in three melanoma cell lines. We found that downregulation of GRP78 led to inhibition of autophagy, cell cycle arrest in the G0/G1 phase, and activation of caspase-7-induced apoptosis, and this was affected by the initial autophagy level. Moreover, inhibition of GRP78 mitigated the combined TMZ and chloroquine effect. Our data revealed that autophagy inhibition through downregulation of ER stress response could overcome resistance to TMZ treatment in melanoma cells with a high basal level of autophagy treatment, which makes this combination a potential potent antitumor treatment for metastatic melanoma.

journal_name

Oncol Rep

journal_title

Oncology reports

authors

Ryabaya O,Prokofieva A,Khochenkov D,Abramov I,Zasedatelev A,Stepanova E

doi

10.3892/or.2018.6430

subject

Has Abstract

pub_date

2018-07-01 00:00:00

pages

385-394

issue

1

eissn

1021-335X

issn

1791-2431

journal_volume

40

pub_type

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