Curcumin enhances the efficacy of chemotherapy by tailoring p65NFκB-p300 cross-talk in favor of p53-p300 in breast cancer
Authors: Gouri Sankar Sen
Pallab Ray
Shilpi Saha
Arindam Bhattacharya
Pushpak Bhattacharjee
Gaurisankar Sa
Debaprasad Mandal
Dewan Md Sakib Hossain
Samit Chattopadhyay
Tanya Das
Suchismita Mohanty
Shuvomoy Banerjee
Juni Chakraborty
Sankar Bhattacharyya
Journal: Journal of Biological Chemistry (2011)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Breast cancer cells; drug resistance; NFκB; SMAR1; IkBα
Affiliations: Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Scheme VII M, Kolkata 700054, India.

Abstract:  Breast cancer cells often develop multiple mechanisms of drug resistance during tumor progression, which is the major reason for the failure of breast cancer therapy. High constitutive activation of NFκB has been found in different cancers, creating an environment conducive for chemotherapeutic resistance. Here we report that doxorubicin-induced SMAR1-dependent transcriptional repression and SMAR1-independent degradation of IkBα resulted in nuclear translocation of p65NFκB and its association with p300 histone acetylase and subsequent transcription of Bcl-2 to impart protective response in drug-resistant cells. Consistently SMAR1-silenced drug-resistant cells exhibited IkBα-mediated inhibition of p65NFκB and induction of p53-dependent apoptosis. Interestingly, curcumin pretreatment of drug-resistant cells alleviated SMAR1-mediated p65NFκB activation and hence restored doxorubicin sensitivity. Under such anti-survival condition, induction of p53-p300 cross-talk enhanced the transcriptional activity of p53 and intrinsic death cascade. Importantly, promyelocyte leukemia-mediated SMAR1 sequestration that relieved the repression of apoptosis-inducing genes was indispensable for such chemo-sensitizing ability of curcumin. A simultaneous decrease in drug-induced systemic toxicity by curcumin might also have enhanced the efficacy of doxorubicin by improving the intrinsic defense machineries of the tumor-bearer. Overall, the findings of this preclinical study clearly demonstrate the effectiveness of curcumin to combat doxorubicin-resistance. We, therefore, suggest curcumin as a potent chemo-sensitizer to improve the therapeutic index of this widely used anti-cancer drug. Taken together, these results suggest that curcumin can be developed into an adjuvant chemotherapeutic drug. 

Retracted: No

PubPeer comments:
 1. Fig 1, Doxorubicin, and Annexin V-PE both fall in FL-2. How did the authors acquire the flow cytometry? 2. Fig 2, PI, and doxorubicin both are very close when it comes to microscopy. DAPI would have been a great option. , 
 Fig4 ![file] Fig 4A and Fig 4B: The input DNA appears to be reused in Fig 4A and 4B. Of note that the promoters were different and the Ip was different. The Fig 4a showed Ip p53 and the Fig 4b showed Ip p65. Could authors clarify these disparities? , 
 #2 Presumably, the IPs were done with the same aliquots of lysate (i.e., a plate was lysed, sonicated, and then aliquoted for the various IPs). The inputs would have been taken from the lysate before it was divided for IP. The promoters and antibodies used for the IP is not relevant when you re looking at the input. , 
 #3 I agree your point that promoter and antibodies may be irrelevant, but, it seems that the authors have showed the same DNA which they measured after the lysates were made in two separate experiments. In general, chromatin immunoprecipitations are performed using ChIP-validated antibodies and ChIP-Grade Protein G Magnetic Beads. After reversal of protein-DNA cross-links, the DNA is purified using DNA purification spin columns, allowing for easy and efficient recovery of DNA and removal of protein contaminants without the need for phenol chloroform extractions and ethanol precipitations. The enrichment of particular DNA sequences during immunoprecipitation can be analyzed by a variety of methods, including standard PCR, quantitative real-time PCR, or amplification for ChIP on chip, sequencing or cloning techniques. This kit is compatible with ChIP-seq. In this setting, I guess, the DNA may look different if authors did PCR twice. Thank you ,