Eukaryotic initiation factor 5A2 mediates hypoxia-induced autophagy and cisplatin resistance

Abstract

Hypoxia-induced cisplatin resistance is a major challenge during non-small cell lung cancer (NSCLC) treatment. Based on previous studies, we further explored the effect of eukaryotic initiation factor 5A2 (eIF5A2) in hypoxia-induced cisplatin resistance. In this study, we found that autophagy and cisplatin resistance were increased under hypoxic conditions in three different NSCLC cell lines. Compared with that under normoxic conditions, dramatic upregulation of eIF5A2 and hypoxia inducible factor 1 subunit alpha (HIF-1α) levels were detected under hypoxia exposure. Small interfering RNA silencing of HIF-1α resulted in decreased expression of eIF5A2, indicating that eIF5A2 acts downstream of HIF-1α. In addition, the expression of eIF5A2 was significantly higher in NSCLC tumors compared with that in normal tissues. RNA silencing-mediated downregulation of eIF5A2 decreased hypoxia-induced autophagy, thereby reducing hypoxia-induced cisplatin resistance in NSCLC cells. The roles of eIF5A2 in cisplatin resistance were further validated in vivo. Combined treatment using eIF5A2-targeted downregulation together with cisplatin significantly inhibited tumor growth compared with cisplatin alone in the subcutaneous mouse model. In conclusions, eIF5A2 overexpression is involved in hypoxia-induced autophagy during cisplatin resistance. We suggest that a combination of eIF5A2 targeted therapy and cisplatin chemotherapy is probably an effective strategy to reverse hypoxia-induced cisplatin resistance and inhibit NSCLC development.

The PRMT5 inhibitor C9 mitigates hypoxia‐induced carboplatin resistance in lung cancer by inducing autophagy

“…Autophagy, an evolutionarily conserved degradation process, is closely associated with the cellular stress response. Several studies have focused on the impact of hypoxia‐induced autophagy in cancer cells (Xu et al, 2022). Hypoxia‐induced HIF1α activation regulates the expression of genes, including BNIP3 and BNIP3L , that are involved in glucose metabolism, angiogenesis, and autophagy (X. Li et al, 2019; Zhao et al, 2012).…”

Nanomedicine Strategies in Conquering and Utilizing the Cancer Hypoxia Environment

“…111 Xu et al found that overexpression of eukaryotic initiation factor 5A2 (eIF5A2) is connected to hypoxia-induced autophagy during cisplatin resistance. 112 Therefore, combining eIF5A2 targeted therapy with cisplatin chemotherapy may be a viable approach for treating hypoxia-induced cisplatin resistance and preventing the growth of NSCLC. Liu et al found that hypoxic conditions resulted in an elevated level in xeroderma pigmentosum group C, a crucial DNA damage recognition protein associated with nucleotide excision repair, which helped to cause cisplatin resistance.…”

“…Moreover, hypoxia-induced overexpression of PKM2 reprogrammed cancer-associated fibroblasts (CAFs) to create an acidic TME encouraging the growth and cisplatin resistance of NSCLC cells . Xu et al found that overexpression of eukaryotic initiation factor 5A2 (eIF5A2) is connected to hypoxia-induced autophagy during cisplatin resistance . Therefore, combining eIF5A2 targeted therapy with cisplatin chemotherapy may be a viable approach for treating hypoxia-induced cisplatin resistance and preventing the growth of NSCLC.…”

Fisetin, a dietary flavonoid, increases the sensitivity of chemoresistant head and neck carcinoma cells to cisplatin possibly through HSP90AA1/IL‐17 pathway

“…The development of DDP‐resistance is accompanied by a series of abnormal gene expressions. For example, overexpression of eIF5A2 was associated with DDP‐resistance in lung cancer (Xu et al, 2022). Likewise, overexpression of REG4 contributed to DDP‐resistance in ovarian cancer (Xiang et al, 2022).…”

“…The development of DDP-resistance is accompanied by a series of abnormal gene expressions. For example, overexpression of eIF5A2 was associated with DDP-resistance in lung cancer (Xu et al, 2022).…”