CURCUMIN SUPPRESSES LUNG CANCER CELL GROWTH BY MODULATING THE LIN28/let-7a/α7 NICOTINIC ACETYLCHOLINE RECEPTOR (α7nAChR) REGULATORY AXIS

Curcumin is a bioactive compound with antitumor effects, although its molecular mechanisms in lung cancer remain incompletely understood. The LIN28/let-7 regulatory system is involved in post-transcriptional gene regulation and cancer progression, with LIN28 negatively regulating let-7a expression and maturation. Curcumin has been reported to negatively regulate LIN28 expression, suggesting that modulation of this pathway may contribute to its antitumor effects. In addition, let-7a has been reported to regulate CHRNA7, which encodes the α7 nicotinic acetylcholine receptor (α7nAChR). However, the functional relevance of this regulatory interaction in cancer and its potential contribution to the antitumor effects of curcumin in lung cancer remain unknown. This study investigated the involvement of this pathway in the response of A549 human lung adenocarcinoma cells to curcumin. A549 cells were treated with curcumin, and cell viability, proliferation, clonogenic growth, migration, and chemosensitivity were evaluated using colorimetric and cell-based assays. LIN28A, LIN28B, let-7a, and CHRNA7 expression were assessed by reverse transcription quantitative PCR (RT-qPCR). To assess pathway function, let-7a activity was inhibited using an anti-let-7a inhibitor and overexpressed using a mimic, while CHRNA7 was overexpressed using a construct lacking the endogenous let-7a-responsive 3′ untranslated region (3′UTR). Curcumin treatment reduced LIN28A and LIN28B expression, increased let-7a levels, and decreased CHRNA7 expression. These changes were accompanied by reduced malignant phenotypes, including decreased Ki-67-positive cells, colony formation, and migration. Inhibition of let-7a significantly increased cell viability, proliferation, Ki-67 expression, and clonogenic growth following curcumin treatment, indicating that let-7a contributes to the antiproliferative response. However, this rescue was partial, suggesting that additional mechanisms contribute to curcumin-induced growth inhibition. Consistent with this, let-7a inhibition did not significantly alter the antimigratory effect of curcumin. CHRNA7 overexpression partially attenuated the inhibitory effects of curcumin, including under combined curcumin and paclitaxel treatment. Furthermore, let-7a overexpression reduced endogenous CHRNA7 expression and decreased cell viability and proliferation. Restoration of CHRNA7 independently of let-7a regulation abolished these effects, supporting CHRNA7 as a functional downstream mediator of let-7a. Together, these findings support a model in which curcumin modulates the LIN28/let-7a/α7nAChR axis as one mechanism contributing to its antiproliferative activity in A549 lung adenocarcinoma cells, while additional pathways likely mediate other cellular effects, including migration. Importantly, our findings provide, to our knowledge, the first functional evidence of a let-7a/α7nAChR regulatory interaction in a cancer model, identifying α7nAChR as a downstream mediator of let-7a activity and linking this interaction to the antiproliferative effects of curcumin. This study was supported by the São Paulo State Research Foundation (FAPESP) [grant number: 2023/11144-5] and the National Council for Scientific and Technological Development (CNPq) [grant number: 151732/2024-8].