The TGFβ1-FOXM1-HMGA1-TGFβ1 positive feedback loop increases the cisplatin resistance of non-small cell lung cancer by inducing G6PD expression

Platinum-based chemotherapy is still widely applied for the treatment of advanced non-small cell lung cancer (NSCLC). However, acquired chemoresistance compromises the curative effect of this drug. In this study, we found that glucose-6-phosphate dehydrogenase (G6PD), a critical enzyme of the pentose phosphate pathway, contributed to cisplatin resistance in NSCLC. The experimental results showed that transforming growth factor beta 1 (TGF beta 1) increased the expression of G6PD by activating the forkhead box protein M1-high mobility group AT-hook 1-G6PD (FOXM1-HMGA1-G6PD) transcriptional regulatory pathway, in which TGF beta 1 inhibited the ubiquitination and degradation of FOXM1 protein. Additionally, HMGA1 induced TGF beta 1 expression, and neutralized TGF beta 1 in the culture medium downregulated HMGA1 levels, suggesting the existence of a TGF beta 1-FOXM1-HMGA1-TGF beta 1 positive feedback loop and its role in maintaining G6PD expression. Further investigations showed that exogenous TGF beta 1 enhanced the cisplatin resistance of NSCLC cells, while disrupting the FOXM1-HMGAl-G6PD pathway, thereby sensitizing the cells to cisplatin. Consistently, the TGF beta 1-FOXM1-HMGA1-G6PD axis was confirmed in NSCLC tissues, and overactivation of this axis predicted poor survival in NSCLC patients. Collectively, the results of this study demonstrate that the TGF beta 1-FOXM1-HMGA1-TGF beta 1 positive feedback loop plays a crucial role in the cisplatin resistance of NSCLC by upregulating the expression of G6PD, providing a potential therapeutic target to restore chemosensitivity in cisplatin-resistant NSCLC.