Bortezomib/proteasome inhibitor triggers both apoptosis and autophagy-dependent pathways in melanoma cells
Authors: Simeon Santourlidis
Benjamin B O W Porzig
Denis Selimovic
Mohamed Hassan
Foued Ghanjati
Youssef Haikel
Mutmid Ahmad
Helene E Badura
Abdelouahid El-Khattouti
Journal: Cellular Signalling (2013)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Endoplasmic reticulum stress; Mitochondrial dysregulation; Bortezomib; Apoptosis; Noxa
Affiliations: Institut National de la Santé et de la Recherche Médicale, U 977, France.

Abstract:  Generally, both endoplasmic reticulum (ER) stress and mitochondrial dysregulation are a potential therapeutic target of anticancer agents including bortezomib. The treatment of melanoma cells with bortezomib was found to induce apoptosis together with the upregulation of Noxa, Mcl-1, and HSP70 proteins, and the cleavage of LC3 and autophagic formation. Also, bortezomib induced ER-stress as evidenced by the increase of intracellular Ca(2+) release. In addition, bortezomib enhanced the phosphorylation of inositol-requiring transmembrane kinase and endonuclease 1α (IRE1α), apoptosis signal-regulating kinase 1 (ASK1), c-jun-N-terminal kinase (JNK) and p38, and the activation of the transcription factors AP-1, ATF-2, Ets-1, and HSF1. Bortezomib-induced mitochondrial dysregulation was associated with the accumulation of reactive oxygen species (ROS), the release of both apoptosis inducing factor (AIF) and cytochrome c, the activation of caspase-9 and caspase-3, and cleavage of Poly (ADP-ribose) polymerase (PARP). The pretreatment of melanoma cells with the inhibitor of caspase-3 (Ac-DEVD-CHO) was found to block bortezomib-induced apoptosis that subsequently led to the increase of autophagic formation. In contrast, the inhibition of ASK1 abrogated bortezomib-induced autophagic formation and increased apoptosis induction. Furthermore, the inhibition of JNK, of HSP70 also increased apoptosis induction without influence of bortezomib-induced autophagic formation. Based on the inhibitory experiments, the treatment with bortezomib triggers the activation of both ER-stress-associated pathways, namely IRE1α-ASK1-p38-ATF-2/ets-1-Mcl-1, and IRE1α-ASK1-JNK-AP-1/HSF1-HSP70 as well as mitochondrial dysregulation-associated pathways, namely ROS-ASK1-JNK-AP-1/HSF1-HS70, and AIF-caspase-3-PARP and Cyt.c, and caspase-9-caspase-3-PARP. Taken together, our data demonstrates for the first time the molecular mechanisms, whereby bortezomib triggers both apoptosis and autophagic formation in melanoma cells. 

Retracted: No

PubPeer comments:
 May 2015 Megacorrection found here: https: www.sciencedirect.com science article pii S0898656815000327 It reads:  The authors would like to apologize for any inconvenience caused. The authors regret that there were errors in Figs. 1A, 1C, 5D, 6B, 6C of the above publication. The corrected versions of the figures are reproduced here. The corrections do not influence either the validity of the published data or the conclusions described in the article. We apologize for these mistakes. There are no details on the errors. But taking a look at the original and corrected figures, we can see some of the original panels appear to have been switched. * Figure 1A. The corrected figure has the two Bortezomib panels switched (red arrows) ![file] * Figure 1C. The corrected figure has the a flipped version of the PARP panel (shown with blue arrows). ![file] * Figure 5D. The correction shows different conditions for the last two lanes (pink boxes). ![file] * Figure 6B and 6C. The correction replaces two empty cells with a  - (orange boxes). ![file] , 
 Unfortunately, this megacorrection did not address a possible duplication in Figure 2B. * Cyan boxes: the Bort+ A375 and BLM panels appear to overlap. Could the authors please check and re-assess if all these errors still do not affect the validity of the conclusions? ![file] ,