Targeting cPLA2α inhibits gastric cancer and augments chemotherapy efficacy via suppressing Ras/MEK/ERK and Akt/β-catenin pathways.

BACKGROUND

Cytosolic phospholipase A2alpha (cPLA2α), an enzyme that is responsible for the hydrolysis of membrane phospholipids, is a key mediator of tumor transformation, progression and metastasis. The role of cPLA2α in gastric cancer has not been revealed.

METHODS

cPLA2α expression was analyzed using RT-PCR and immunohistochemistry approaches in gastric cancer patient samples (n = 26) and multiple cell lines (n = 7). cPLA2α function was studied using plasmid overexpression and siRNA knockdown approaches in SNU-1, MKN-74 and MKN-45 cell lines. The downstream effectors of cPLA2α were determined using biochemical assays.

RESULTS

cPLA2α upregulation is a common feature in gastric cancer patients, particularly those with metastasis. cPLA2α overexpression is sufficient to promote gastric cancer cell growth and migration, and confer chemo-resistance. cPLA2α depletion is active against gastric cancer via inhibiting growth and migration, and inducing apoptosis in gastric cancer cells. Of note, cPLA2α depletion augments efficacy of chemotherapy. Mechanistic studies confirm that cPLA2α regulates gastric cancer biological activities via mainly regulating Ras/MEK/ERK and possibly Akt/β-catenin pathways. Pearson correlation coefficient analysis also suggests a moderate positive correlation between cPLA2α and RAS in gastric cancer.

CONCLUSIONS

Our work demonstrates cPLA2α inhibition as a therapeutic strategy to overcome chemo-resistance and highlights the association of cPLA2α and Ras in gastric cancer.