ARHGAP6 Promotes Apoptosis and Inhibits Glycolysis in Lung Adenocarcinoma Through STAT3 Signaling Pathway

OBJECTIVE: Constitutively activated signal transducer and activator of transcription 3 (STAT3) has been linked to cisplatin (DDP)-resistance in a wide range of cancers. Recent work has indicated that Rho GTPase-activating protein 6 (ARHGAP6) promotes cell cycle arrest and apoptosis in cervical and breast cancers. However, the role of ARHGAP6 in lung adenocarcinoma and DDP-resistance remains unknown. MATERIALS AND METHODS: Bioinformatic analysis, quantitative RT-PCR and IHC staining were used to explore ARHGAP6 expression patterns in The Cancer Genome Atlas (TCGA) dataset and patient samples. Statistical analysis was performed to establish the association of ARHGAP6 expression with the resistance to DDP-based chemotherapy in lung adenocarcinoma patients. Functional assays were then conducted to examine the effect of ARHGAP6 on the apoptosis and glycolysis in DDP-resistant/sensitive A549/DPP cells in vitro. Finally, the effects of ARHGAP6 on the chemosensitivity of DDP were explored in vivo. RESULTS: We show that decreased ARHGAP6 levels are a reliable marker of lung adenocarcinoma across published datasets, cell culture lines, and clinical samples. Low ARHGAP6 expression was linked to decreased apoptosis and increased metabolic activity, which highlights ARHGAP6’s role as a tumor suppressor. Furthermore, activated p-STAT3 levels increased dramatically in the absence of ARHGAP6, which suggests that ARHGAP6 can inhibit the STAT3 pathway. In agreement with previous studies that linked p-STAT3 levels to DDP-resistance, our in vitro and in vivo data indicate that tumors became more resistant to DDP-therapy with reduced ARHGAP6 levels and an associated increase in p-STAT3. CONCLUSION: ARHGAP6 presents a novel study target for overcoming p-STAT3-associated DDP-resistance in lung adenocarcinoma and potentially other cancers.