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

IF 5.7 2区医学 Q1 Medicine

Cancer Science Pub Date : 2025-02-14 DOI:10.1111/cas.70019

Guosen Wang, Yi Cao, Tengcheng Hu, Zhengqing Cai, ChuanPing Chen, Qilong Geng, Xinyu Luo, Yang Liu, Weijie Wang, Jiabin Jin, Weiwei Sheng

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引用次数: 0

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.

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来源期刊

Cancer Science ONCOLOGY-

CiteScore

9.90

自引率

3.50%

发文量

406

审稿时长

17 weeks

期刊介绍： Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.