Regulation of apoptosis in human melanoma and neuroblastoma cells by statins, sodium arsenite and TRAIL: a role of combined treatment versus monotherapy
Authors: Vladimir N Ivanov
Tom K Hei
Journal: APOPTOSIS (2011)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: melanoma cells; sodium arsenite; statins; heme oxygenase-1 (HO-1); cyclooxygenase-2 (COX-2)
Affiliations: Department of Radiation Oncology, Center for Radiological Research, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. 

Abstract:  Treatment of melanoma cells by sodium arsenite or statins (simvastatin and lovastatin) dramatically modified activities of the main cell signaling pathways resulting in the induction of heme oxygenase-1 (HO-1) and in a downregulation of cyclooxygenase-2 (COX-2) protein levels. Through heme degradation and the production of carbon monoxide and biliverdin, HO-1 plays a protective role in different scenario of oxidative stress followed by mitochondrial apoptosis. Both sodium arsenite and statins could be efficient inducers of apoptosis in some melanoma cell lines, but often exhibited only modest proapoptotic activity in others, due to numerous protective mechanisms. We demonstrated in the present study that treatment by sodium arsenite or statins with an additional inhibition of HO-1 expression (or activation) caused a substantial upregulation of apoptosis in melanoma cells. Sodium arsenite- or statin-induced apoptosis was independent of BRAF status (wild type versus V600E) in melanoma lines. Monotreatment required high doses of statins (20-40 ŒºM) for effective induction of apoptosis. As an alternative approach, pretreatment of melanoma cells with statin at decreased doses (5-20 ŒºM) dramatically enhanced TRAIL-induced apoptosis, due to suppression of the NF-Œ∫B and STAT3-transcriptional targets (including COX-2) and downregulation of cFLIP-L (a caspase-8 inhibitor) protein levels. Furthermore, combined treatment with sodium arsenite and TRAIL or simvastatin and TRAIL efficiently induced apoptotic commitment in human neuroblastoma cells. In summary, our findings on enhancing effects of combined treatment of cancer cells using statin and TRAIL provide the rationale for further preclinical evaluation. 

Retracted: No

PubPeer comments:
 Figure 5. Much more similar than you would expect.  , 
 #1 Thank you for your comment. It seems to me that I have done quite bad mistake with caspase-9 western for WM793 cells. I shall remove this western from paper and change for a proper one. I quite often use both side of X-ray film for taking images of western after ECL. As a result, I have two mirror images. I guess I mistakenly identified caspase-8 p56 mirror image of WM9 cells as caspase-9 p47 direct image of WM793. Thank you again. , 
 It take quite long time to fix an error with caspase-9 Western for WM793 melanoma. It was necessary to restore WM793 cell culture after several years in liquid nitrogen. Then came COVID time... Finally, the original Western for caspase-9 in WM793 cells and corrected Figure 5:    , 
 #3 I was expecting to see this published as a correction, but was unable to locate it. Upon reviewing the  Corrected Figure 5B, I believe there is still at least one portion of a band that has been used to represent different conditions, after horizontal flip. ***  , 
 After revealing the errors in Western blots of caspase-9 in WM793 and WM9 melanoma cells, we decided to repeat Western blot analysis. It took a time to restore melanoma culturing, which was stopped in the lab almost 7 years ago. Finally, we performed new experiments with these melanoma cells and fixed western blot data for caspase-9. COVID time restriction slow done our communication with Apoptosis journal regarding a correction of Figure 5. Hopefully, it will be done soon. However, I am sending the final correction of this Figure. Thanks for your permanent interest in our Apoptosis-2011 paper, your time, and attention.  , 
 #5 Can the authors please provide the uncropped scans? , 
 #6 Sure, it was submitted to Apoptosis editorial office. , 
 Yes, there are original scans:  ,