ATP11B mediates platinum resistance in ovarian cancer
Authors: Archana S Nagaraja
Hua Wang
Mary J C Hendrix
Cristian Rodriguez-Aguayo
Paul S Meltzer
Lingegowda S Mangala
Robert R Langley
Tamas A Gonda
Nicholas B Jennings
Cristina Ivan
J B Halder
Rosemarie Schmandt
Gabriel Lopez-Berestein
Jeremy E Coffin
Justin Bottsford-Miller
Ju-Seog Lee
Sang Bae Kim
Chunhua Lu
Zahid H Siddik
Kshipra M Gharpure
Anil K Sood
Menashe Bar-Eli
Margaret S Halleck
Yu Kang
Rajesha Rupaimoole
Myrthala Moreno-Smith
William Bornman
Guillermo N Armaiz
Behrouz Zand
Pablo E Vivas-Mejia
Journal: Journal of Clinical Investigation (2013)
Discipline: CLINICAL MEDICINE
Keywords: Platinum compounds; resistance mechanisms; ATP11B; cisplatin resistance; ovarian cancer
Affiliations: Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Abstract:  Platinum compounds display clinical activity against a wide variety of solid tumors; however, resistance to these agents is a major limitation in cancer therapy. Reduced platinum uptake and increased platinum export are examples of resistance mechanisms that limit the extent of DNA damage. Here, we report the discovery and characterization of the role of ATP11B, a P-type ATPase membrane protein, in cisplatin resistance. We found that ATP11B expression was correlated with higher tumor grade in human ovarian cancer samples and with cisplatin resistance in human ovarian cancer cell lines. ATP11B gene silencing restored the sensitivity of ovarian cancer cell lines to cisplatin in vitro. Combined therapy of cisplatin and ATP11B-targeted siRNA significantly decreased cancer growth in mice bearing ovarian tumors derived from cisplatin-sensitive and -resistant cells. In vitro mechanistic studies on cellular platinum content and cisplatin efflux kinetics indicated that ATP11B enhances the export of cisplatin from cells. The colocalization of ATP11B with fluorescent cisplatin and with vesicular trafficking proteins, such as syntaxin-6 (STX6) and vesicular-associated membrane protein 4 (VAMP4), strongly suggests that ATP11B contributes to secretory vesicular transport of cisplatin from Golgi to plasma membrane. In conclusion, inhibition of ATP11B expression could serve as a therapeutic strategy to overcome cisplatin resistance. 

Retracted: No

PubPeer comments:
 Fig 3B- Empty liposome and control siRNA IHC staining (PCNA) looks like same slide after adjustment. ![file] , 
 The more I read, the more I get interesting results from one of famous labs. ![file] , 
 Can we give any notice to all authors or to corresponding author only through this site before go to Journal editors? , 
 #2 Dearest Sea Snail, When it comes to setting the scientific record straight, there is none better than the JCI. They take a very dim view of image duplications in their published papers. I think it is safe to say that they will be immensely displeased to have been duped into republishing ten images that were published four years earlier. Images for which they donu2019t have the copyright... If you didnu2019t already do so, then you are strongly encouraged to contact the journal, anonymously if you prefer. , 
 An expression of concern has been posted: https: www.jci.org articles view 122301 , 
 2021 corrigendum. https: www.jci.org articles view 149893 The Editors previously posted an Expression of Concern for this article regarding images in Figure 3B that appeared to be the same as images that were previously published in a 2009 Clinical Cancer Research paper with different sample labels (doi: 10.1158 1078-0432.CCR-08-2306). Additionally, the empty liposome and control siRNA PCNAu2013stained panels were noted to appear to be the same. An institutional review committee concluded that the errors in Figure 3B were inadvertent and recommended correction. The authors provided the correct version of Figure 3B with data obtained from a repeated experiment. That correct version is shown below. , 
 I do not see that an image overlap in Figure 5A and 5D has yet been addressed (green boxes). The difference between intentional misconduct, inadvertent errors, and or poor record keeping can be difficult for outside readers to determine. *** ![file] , 
 #7 It appears that this was fixed in an earlier correction: Original citation: J Clin Invest. 2013;123(5):2119u20132130. doi:10.1172 JCI65425. Citation for this corrigendum: J Clin Invest. 2013;123(12):5411. doi:10.1172 JCI73904. The legend for Figure 5 did not disclose that the images presented in part A were duplicated as the no treatment control for the cisplatin experiment shown in parts D and E. The authors wish to add the correction below to the legend for Figure 5. The merged immunofluorescence images showing colocalization of ATP11B and STX6 in A2780-PAR and A2780-CP20 cells in A are shown again in D and E to demonstrate localization of ATP11B and STX6 in the absence of cisplatin in A2780-PAR and A2780-CP20 cells. The authors regret the error. ,