Abstract
Reduced sensitivity to chemotherapeutic drugs is almost inevitable in lung adenocarcinoma patients. Thus, understanding the relevant mechanisms is urgent. Positive cofactor 4 (PC4) was at first revealed to be a coactivator of basal transcription. Previous research has shown that PC4 participates in various cellular processes in normal and malignant cells. However, it is still unknown whether PC4 participates in altering the lung adenocarcinoma cell sensitivity to chemotherapy, and the relevant mechanisms remain to be explained. In this study, we discovered that PC4 was overexpressed in cisplatin-resistant lung adenocarcinoma cells. PC4 decreased cisplatin's cytotoxic effects on lung adenocarcinoma in vivo and in vitro. Furthermore, PC4 positively correlated with SOX9 in multiple cancers. PC4 was an upstream regulator of SOX9 in lung adenocarcinoma. Furthermore, PC4 mediated lung adenocarcinoma cell sensitivity to the HIF-PH inhibitor DMOG and the mTOR inhibitor rapamycin, and PC4 mediated the synergistic effect of DMOG and cisplatin. Finally, PC4 destabilized HIF-1α upon cisplatin treatment. Our research showed that PC4 participates in mediating lung adenocarcinoma cell sensitivity to multiple drugs. Mechanistically, PC4 governs multiple downstream pathways associated with chemotherapy resistance, including the SOX9 and HIF-1α pathways. Thus, PC4 is a promising chemotherapeutic target in lung adenocarcinoma.
Highlights
Reduced sensitivity to chemotherapeutic drugs is almost inevitable in lung adenocarcinoma (LUAD) therapy
Database, we discovered that Positive cofactor 4 (PC4) was overexpressed in cisplatin-resistant LUAD A549 cells, indicating that PC4 may participate in the regulation of LUAD cell sensitivity to cisplatin
Rough lentivirus infection, PC4 was stably inhibited in PC-9 cells and overexpressed in H1299 cells. e in vitro study revealed the aggressive phenotype PC4 conferred to lung adenocarcinoma cells migration, which is consistent with previous research in other cancer cell types [13, 14]
Summary
Reduced sensitivity to chemotherapeutic drugs is almost inevitable in lung adenocarcinoma (LUAD) therapy. Many genes were discovered as targets to predict the progression or therapeutic response of lung adenocarcinoma [1]. Us, improving lung adenocarcinoma cell sensitivity to chemotherapy is still of great clinical significance. Previous research shows that PC4 participates in a variety of cellular processes, such as DNA repair, DNA replication, transcription, and chromatin organization [6, 9,10,11,12]. PC4 is reported to participate in multiple cancer progressions. Our previous research shows that inhibiting PC4 reduces the lymphatic metastasis of lung adenocarcinoma [8]. The role of PC4 in mediating lung adenocarcinoma cell sensitivity to chemotherapy remains to be explored, and the relevant mechanisms remain to be further elucidated
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