Aspirin enhances cisplatin sensitivity of resistant non-small cell lung carcinoma stem-like cells by targeting mTOR-Akt axis to repress migration

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 Gsk3β that in turn causes destabilization of Snail and β-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.

Aspirin overcomes cisplatin resistance in lung cancer by inhibiting cancer cell stemness

“…The combination was effective at decreasing drug resistance, stemness, and hypoxia in TME. Most of our results are in line with recent literature 20,21 …”

“…Most of our results are in line with recent literature. 20,21 In cisplatin-resistant cell lines, the increased activation of ALDH1 is related to the expression of tumor stem cell markers. 22 Lung cancer cells expressing CD44 are enriched for stem-like properties, and CD44-positive cells show a higher level of expression for pluripotency markers (Oct-4, Sox-2) and increased resistance to cisplatin.…”

Cyclooxygenase-2 mediates gefitinib resistance in non-small cell lung cancer through the EGFR/PI3K/AKT axis

“…Next, we investigated the effects of COX-2 of an array of known pro-oncogenic signaling pathways. We observed robust AKT activation in COX-2 overexpressing cells and a loss of MMP expression and PI3K signaling upon COX-2 silencing confirming a role for MMPs and AKT in NSCLC metastasis occurrence and development [40][41][42][43]. We further demonstrated the ability of COX-2 to bind to the EGFR which, in turn, activated EGFR and enhanced PI3K signaling.…”

Signaling, metabolism, and cancer: An important relationship for therapeutic intervention

“…A study has shown that aspirin, by downregulation of GLUT1 and weakening glucose uptake as well as reducing the level of oxidizing species, decreases the growth of liver cancer cells (Y. Liu, Feng, et al, 2019). Aspirin can attenuate AKT/mTOR signaling in lung carcinoma cells that in turn causes impairment of Wnt/Bcatenin signaling pathway (Khan et al, 2019). As presented in Figures 2 and 3, these signaling pathways have considerable effects on metabolism.…”