Aspirin enhances cisplatin sensitivity of resistant non-small cell lung carcinoma stem-like cells by targeting mTOR-Akt axis to repress migration
Authors: Debomita Sengupta
Poulami Khan
Shruti Banerjee
Apoorva Bhattacharya
Tanya Das
Arghya Adhikary
Journal: Scientific Reports (2019)
Discipline: Multidisciplinary
Keywords: chemotherapeutic regimens; metastasis; non-small cell lung carcinoma (NSCLC); cancer stem cells (CSCs); migration potential
Affiliations: Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700054, India., Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, JD-2, Sector III, Salt Lake, Kolkata, 700098, West Bengal, India., Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, 700054, India. .

Abstract:  Conventional chemotherapeutic regimens are unable to prevent metastasis of non-small cell lung carcinoma (NSCLC) thereby leaving cancer incurable. Cancer stem cells (CSCs) are considered to be the origin of this therapeutic limitation. In the present study we report that the migration potential of NSCLCs is linked to its CSC content. While cisplatin alone fails to inhibit the migration of CSC-enriched NSCLC spheroids, in a combination with non-steroidal anti inflammatory drug (NSAID) aspirin retards the same. A search for the underlying mechanism revealed that aspirin pre-treatment abrogates p300 binding both at TATA-box and initiator (INR) regions of mTOR promoter of CSCs, thereby impeding RNA polymerase II binding at those sites and repressing mTOR gene transcription. As a consequence of mTOR down-regulation, Akt is deactivated via dephosphorylation at Ser473 residue thereby activating Gsk3Œ≤ that in turn causes destabilization of Snail and Œ≤-catenin, thus reverting epithelial to mesenchymal transition (EMT). However, alone aspirin fails to hinder migration since it does not inhibit the Integrin/Fak pathway, which is highly activated in NSCLC stem cells. On the other hand, in aspirin pre-treated CSCs, cisplatin stalls migration by hindering the integrin pathway. These results signify the efficacy of aspirin in sensitizing NSCLC stem cells towards the anti-migration effect of cisplatin. Cumulatively, our findings raise the possibility that aspirin might emerge as a promising drug in combinatorial therapy with the existing chemotherapeutic agents that fail to impede migration of NSCLC stem cells otherwise. This may consequently lead to the advancement of remedial outcome for the metastatic NSCLCs. 

Retracted: No

PubPeer comments:
 Fig 2  Could authors please check the DAPI and Myr-Akt panels? It looks like the cells in DAPI panel and Myr-Akt panel are different. The authors used these panel for b-Catenin staining. , 
 We are really thankful to you for pointing out our unintentional presentation of photos from another set while we have all the photos of the same set. So although the results and conclusions remain same as we claimed - we are sorry for this mistake that we somehow missed during final check up.  We are truly grateful to you for your valuable mention. In fact, in Figure 2E, there is an unintentional mixing up of photos from two different sets of data. In fact, DAPI and gray scale images in the Myr-Akt panel (red highlighted box) was mistakenly included from one set whereas those of u03b2-catenine and merged images were from another set. So although the results and conclusions remain same as we claimed - we are sorry for this unintentional mistake that we somehow missed during final check-up. We are now attaching the JPEG images of old Figure 2E that has been published, as well as the corrected Figure 2E containing all the data from a single set (keeping those of u03b2-catenine and merged images fixed) for your kind perusal. In case of both of these the panels of concern, i.e., the DAPI and gray scale panels are highlighted with red boxes. Hope you will understand that this is our honest confession since we already had all the proper data in our possession.  **Figure 2(E)**: Confocal microscopic images show the expression of u03b2-catenin, in A549 control as well as DN-Akt and Myr-Akt transfected spheroids with DAPI staining for nucleus. Scale bar 50 u00b5m; magnifcation 40u00d7. Values are meanu00b1SEM of three independent experiments in each case or representative of typical experiment *p 0.01,***p 0.001 Although the completely unintentional mistake made during data processing and presentation was there, we would like to mention that in that published article, we also provided strong supportive flowcytometry data (Figure 2H) which validated that the difference could also be seen in protein level thereby supporting our claims in Figure 2E. Therefore, we would like to draw the kind attention of readers that though the conclusion remains same after this mistake, we would surely correct the images by submitting erratum and for this we have already contacted the journal. , 
 Thank you Dr. Das for correcting the images. I look forward to see your erratum. We all understand that mistakes occur and we take it. I also would appreciate if you look into few of your other publications and clarify the issues. , 
 #3 I am scrutinizing those and shall get back as soon as possible. ,