PLA2G16 deficiency enhances oxaliplatin sensitivity in colorectal cancer

Colorectal cancer (CRC) is a common malignancy with an increasing incidence among younger populations. Oxaliplatin (OXA) is a first-line chemotherapeutic agent for CRC; however, the development of chemoresistance severely limits its clinical efficacy. The molecular mechanisms underlying OXA resistance remain incompletely understood. This study aimed to investigate the role of phospholipase A2 group XVI (PLA2G16) in oxaliplatin sensitivity in CRC and to explore potential underlying biological processes.

PLA2G16-deficient CRC cell lines were generated, and OXA sensitivity was evaluated using cell proliferation, colony formation, apoptosis, and cell cycle assays. Transcriptomic and lipidomic analyses were performed to investigate PLA2G16-associated pathways and lipid metabolic alterations. Autophagy-related markers were assessed by Western blot and immunohistochemistry (IHC). In vivo CRC xenograft models were established to evaluate tumor growth, tumor weight, and protein expression in tumor tissues following OXA treatment.

PLA2G16 deficiency significantly enhanced OXA sensitivity in CRC cells, as evidenced by reduced cell proliferation, decreased colony formation, increased apoptosis, and altered cell cycle distribution. Integrated transcriptomic and lipidomic analyses revealed that PLA2G16 depletion markedly affected autophagy-related signaling pathways and lipid metabolism. Specifically, increased LC3BII and p62 expression, enhanced autophagosome formation, and significant alterations in TAG, PC, and PE lipid profiles were observed. In vivo, PLA2G16 deficiency markedly enhanced the antitumor efficacy of OXA, resulting in reduced tumor growth and tumor weight, accompanied by altered expression of autophagy-related proteins in tumor tissues.

This study demonstrates that PLA2G16 deficiency enhances oxaliplatin sensitivity in colorectal cancer. These findings suggest that PLA2G16 may serve as a potential target for improving chemotherapy efficacy and provide new insights into the mechanisms underlying oxaliplatin resistance.