PLD2 fuels 5‑fluorouracil resistance in colorectal cancer: Hypoxic hijacking of autophagy unveils a novel therapeutic vulnerability

The present study investigated the relationship between phospholipase D2 (PLD2) and hypoxia‑induced chemoresistance in colorectal cancer (CRC) and elucidated its regulatory mechanisms. The present study demonstrated that increased PLD2 was associated with poor prognosis and chemoresistance in CRC via The University of Alabama at Birmingham cancer data analysis portal and Kaplan‑Meier plotter databases and 5‑fluorouracil (5‑Fu)‑resistant CRC tissues. The protein expression of PLD2, hypoxia‑inducible factor 1 alpha (HIF‑1α), multidrug resistance‑associated protein 2 (MRP2), LC3‑II/I, and Beclin‑1 was markedly upregulated under hypoxia in SW620 and SW480 cells in a time‑dependent manner. Next, SW620 and SW480 cells were transduced with recombinant replication‑deficient adenoviral vectors encoding PLD2‑targeting short hairpin (sh)RNA (Ad‑sh‑PLD2) or PLD2 overexpression (oe) constructs (Ad‑oe‑PLD2), followed by treatment with 5‑Fu, rapamycin (Rapa), or 3‑methyladenine (3‑MA), either alone or in combination. In vitro data revealed that PLD2 promoted hypoxia‑driven 5‑Fu resistance by enhancing autophagy. Decreasing PLD2 expression increased tumor sensitivity to 5‑Fu in a mouse xenograft model, an effect that was reversed by Rapa treatment. In conclusion, the findings suggested that PLD2 is associated with hypoxia‑induced CRC chemoresistance by modulating autophagy, suggesting that PLD2 is a potential new therapeutic target.