A Mutual Interaction Between GSTP1 and p53 Improves the Drug Resistance and Malignant Biology of Pancreatic Cancer.

Abstract

Glutathione S-transferase P1 (GSTP1), a classic tumor biomarker, plays a controversial role in cancer progression. However, its specific role in pancreatic cancer (PC) has rarely been investigated. In the present study, we investigated the function and relationship between GSTP1 and mutant/wild-type p53 (mtp53/wtp53) in PC in vitro and in vivo. Compared with paired adjacent normal pancreas tissue, GSTP1 was downregulated in PC tissue, which was closely correlated with lymph node metastasis, Union for International Cancer Control (UICC) stage, and a better outcome of PC patients, processes dependent on wtp53 rather than mtp53. Moreover, a mutual regulation between GSTP1 and p53 was found in wtp53 PC cells. GSTP1 overexpression inhibited cell proliferation and chemotherapy resistance in vitro via wtp53/p21 and Bax/Bcl2 signaling, which was significantly reversed by wtp53 silencing, and vice versa. Similarly, the coordination of GSTP1 and p53 regulated the invasion and migration of PC cells, which was accompanied by changes in epithelial-mesenchymal transition (EMT) signaling (E-cad, ZO-1 and MMP9). Moreover, GSTP1 overexpression inhibited tumor growth and liver metastasis in vivo, as did high wtp53 and low ki67 expression. Interestingly, GSTP1 did not coimmunoprecipitate with either mtp53 or wtp53 in vitro. However, the wtp53 protein, as a transcription factor, could bind to the GSTP1 DNA promoter to transactivate GSTP1 mRNA expression as demonstrated via a Chip assay. Additionally, GSTP1 promoted the translocation of wtp53 into the nucleus but not mtp53. These results suggest that the positive feedback regulation of GSTP1 and wtp53 plays a significant role in cell proliferation, drug resistance, cell invasion and metastasis in PC.