期刊
CANCER CHEMOTHERAPY AND PHARMACOLOGY
卷 88, 期 4, 页码 689-697出版社
SPRINGER
DOI: 10.1007/s00280-021-04322-1
关键词
cPLA2 alpha; Chemoresistance; Ras/Raf/Mek; Akt/eIF4E; Gastric cancer
资金
- Nature Science Foundation of Hubei Province [2017CFB606]
The study showed that upregulation of cPLA2alpha is common in gastric cancer patients with metastasis, and its overexpression promotes cell growth and migration while its depletion inhibits these processes. Decreasing cPLA2alpha can enhance chemotherapy efficacy by mainly regulating Ras/MEK/ERK and possibly Akt/beta-catenin pathways in gastric cancer cells.
Background Cytosolic phospholipase A2alpha (cPLA2 alpha), an enzyme that is responsible for the hydrolysis of membrane phospholipids, is a key mediator of tumor transformation, progression and metastasis. The role of cPLA2 alpha in gastric cancer has not been revealed. Methods cPLA2 alpha expression was analyzed using RT-PCR and immunohistochemistry approaches in gastric cancer patient samples (n = 26) and multiple cell lines (n = 7). cPLA2 alpha function was studied using plasmid overexpression and siRNA knockdown approaches in SNU-1, MKN-74 and MKN-45 cell lines. The downstream effectors of cPLA2 alpha were determined using biochemical assays. Results cPLA2 alpha upregulation is a common feature in gastric cancer patients, particularly those with metastasis. cPLA2 alpha overexpression is sufficient to promote gastric cancer cell growth and migration, and confer chemo-resistance. cPLA2 alpha depletion is active against gastric cancer via inhibiting growth and migration, and inducing apoptosis in gastric cancer cells. Of note, cPLA2 alpha depletion augments efficacy of chemotherapy. Mechanistic studies confirm that cPLA2 alpha regulates gastric cancer biological activities via mainly regulating Ras/MEK/ERK and possibly Akt/beta-catenin pathways. Pearson correlation coefficient analysis also suggests a moderate positive correlation between cPLA2 alpha and RAS in gastric cancer. Conclusions Our work demonstrates cPLA2 alpha inhibition as a therapeutic strategy to overcome chemo-resistance and highlights the association of cPLA2 alpha and Ras in gastric cancer.
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