AMIGO2 attenuates innate cisplatin sensitivity by suppression of GSDME‐conferred pyroptosis in non‐small cell lung cancer

Abstract

Non‐small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer. Cisplatin is commonly used in the treatment of many malignant tumours including NSCLC. The innate drug sensitivity greatly affects the clinical efficacy of cisplatin‐based chemotherapy. As a plasma membrane adhesion molecule, amphoterin‐induced gene and ORF‐2 (AMIGO2) initially identified as a neurite outgrowth factor has been recently found to play a crucial role in cancer occurrence and progression. However, it is still unclear whether AMIGO2 is involved in innate cisplatin sensitivity. In the present study, we provided the in vitro and in vivo evidences indicating that the alteration of AMIGO2 expression triggered changes of innate cisplatin sensitivity as well as cisplatin‐induced pyroptosis in NSCLC. Further results revealed that AMIGO2 might inhibit cisplatin‐induced activation of (caspase‐8 and caspase‐9)/caspase‐3 via stimulating PDK1/Akt (T308) signalling axis, resulting in suppression of GSDME cleavage and the subsequent cell pyroptosis, thereby decreasing the sensitivity of NSCLC cells to cisplatin treatment. The results provided a new insight that AMIGO2 regulated the innate cisplatin sensitivity of NSCLC through GSDME‐mediated pyroptosis.

Role of AMIGO2 in cancer progression: Novel insights (Review)

“…Furthermore, AMIGO2 likely suppressed cisplatin-induced pyroptosis through modulation of the caspase cascade via activation of the PDK1/Akt (T308) signaling axis. These findings were further validated through in vivo experiments ( 53 ).…”

“…However, the sensitivity of tumor cells to cisplatin can influence the potency of chemotherapy. Chen et al ( 53 ) revealed that AMIGO2 could reduce the sensitivity of NSCLC cells to cisplatin and modulate the effects of cisplatin on lytic cell death. The authors observed that NSCLC cells treated with cisplatin underwent morphological changes, such as becoming rounded and contracted.…”

“…Subsequently, PIP3 binds to Akt and PDK1, and PDK1 phosphorylates the Akt protein, activating downstream signaling pathways such as the mTOR and Bax signaling pathways ( 66 , 67 ), consequently influencing various biological behaviors of cells. Studies have revealed that AMIGO2 could regulate M2 macrophage polarization, angiogenesis and chemotherapy resistance by affecting the PI3K/AKT signaling pathway ( 14 , 36 , 53 ). Nevertheless, the specific molecular mechanisms underlying the interaction between AMIGO2 and PI3K/AKT signaling remain unclear and warrant further exploration.…”

AMIGO2 is a pivotal therapeutic target related to M2 polarization of macrophages in pancreatic ductal adenocarcinoma

“…The correlation of M2 polarization of macrophage and AMIGO2 was identified and validated in both clinical samples and cell lines. Previous studis have reported that AMIGO2 could active PDK1/Akt pathway [ 31 , 32 ], and it is well-known that activation of Akt pathway is a pivotal factor for M2 polarization in macrophage. We speculate that the upregulation of AMIGO2 actives M2 polarization of macrophages through Akt pathway.…”