Oncogenic BRAF induces chronic ER stress condition resulting in increased basal autophagy and apoptotic resistance of cutaneous melanoma

Abstract

The notorious unresponsiveness of metastatic cutaneous melanoma to current treatment strategies coupled with its increasing incidence constitutes a serious worldwide clinical problem. Moreover, despite recent advances in targeted therapies for patients with BRAF V600E mutant melanomas, acquired resistance remains a limiting factor and hence emphasises the acute need for comprehensive pre-clinical studies to increase the biological understanding of such tumours in order to develop novel effective and longlasting therapeutic strategies. Autophagy and ER stress both have a role in melanoma development/progression and chemoresistance although their real impact is still unclear. Here, we show that BRAF V600E induces a chronic ER stress status directly increasing basal cell autophagy. BRAF V600E -mediated p38 activation stimulates both the IRE1/ASK1/JNK and TRB3 pathways. Bcl-XL/Bcl-2 phosphorylation by active JNK releases Beclin1 whereas TRB3 inhibits the Akt/mTor axes, together resulting in an increase in basal autophagy. Furthermore, we demonstrate chemical chaperones relieve the BRAF V600E -mediated chronic ER stress status, consequently reducing basal autophagic activity and increasing the sensitivity of melanoma cells to apoptosis. Taken together, these results suggest enhanced basal autophagy, typically observed in BRAF V600E melanomas, is a consequence of a chronic ER stress status, which ultimately results in the chemoresistance of such tumours. Targeted therapies that attenuate ER stress may therefore represent a novel and more effective therapeutic strategy for BRAF mutant melanoma.

Expression of Autophagy-Related Proteins in Different Types of Thyroid Cancer

“…Specifically, higher expression levels of all autophagy-related proteins were observed in PTCs with the BRAF V600E mutation, compared to those without the BRAF V600E mutation. In support of this finding, previous studies have observed an association between the BRAF V600E mutation and increased autophagy [23,24]. This association may be attributed to multiple factors.…”

Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer

“…Similarly, oncogenic transformation driven by loss of the tumor suppressors p53, PTEN, TSC1 or TSC2 dramatically enhances protein synthesis rates, leading to ER stress (Hart et al, 2012; Namba et al, 2015; Signer et al, 2014). Enhanced protein synthesis and concomitant ER stress are also observed upon overexpression of oncogenic HRAS (G12E), BRAF (V600E), c-Myc or Src (Chen et al, 2014; Corazzari et al, 2015; Denoyelle et al, 2006). Importantly, both the UPR signaling and leukemia development induced by conditional PTEN deletion (Signer et al, 2014) or c-Myc overexpression (Hart et al, 2012) were dramatically reduced or entirely abrogated upon heterozygous deletion of the key translation rate regulator ribosomal protein L24.…”

Prognostic Impact of Autophagy Biomarkers for Cutaneous Melanoma

“…Conversely, oncogenic BRAF induces a chronic ER stress status, resulting in enhanced basal autophagy [as evidenced by increased Atg8-PE/LC3-II (LC3-II) expression], resistance of melanoma cells to apoptosis, and insensitivity to further autophagy induction. This suggests that although melanomas rely on increased innate autophagic activity, BRAF-mutated tumors are resistant to further mTOR-dependant stimulation of autophagy and that while combined inhibition of autophagy with chemotherapy might be a viable therapeutic avenue for BRAF wild-type melanomas, targeted therapies that attenuate ER stress may prove a more effective treatment strategy for BRAF mutant melanomas (12, 18, 19). …”