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DpdtbA-Induced Growth Inhibition in Human Esophageal Cancer Cells Involved Inactivation of the p53/EGFR/AKT Pathway.

ABSTRACT: Esophageal cancer (ESC) is one of the most deadly diseases for human. p53 in most cancers, including ESC cell, is mutated, and the mutated p53 losses its original function and acquires "gain of function" that allows for promoting the hallmarks of cancer, such as antiapoptosis, metastasis, invasion, angiogenesis, and resistance to chemotherapy. Targeting p53 through either introducing wild-type or degrading mutated p53 is an important strategy in cancer therapy. Di-2,2'-pyridine ketone dithiocarbamate s-butyric acid (DpdtbA) has significant growth inhibition against gastric cancer lines in previous study. Similar action in ESC cell lines but a novel molecular mechanism was observed in the present study. The results showed that DpdtbA exhibited an excellent antiproliferative effect for ESC cell lines (IC₅₀ ? 4.5 ± 0.4??M for Kyse 450, 3.2 ± 0.6??M for Kyse 510 cell, and 10.0 ± 0.6??M for Kyse 150) and led to cell cycle arrest at the S phase which correlated to CDK2 downregulation. The mechanistic study suggested that growth inhibition was related to ROS-mediated apoptosis, and ROS production was due to SOD inhibition initiated by DpdtbA rather than occurrence of ferritinophagy. In addition, DpdtbA also induced a downregulation of EGFR, p53, and AKT, which hinted that mutant p53 still played a role in the regulation of its downstream targets. Further study revealed that the downregulation of p53 was through stub1- (chip-) mediated autophagic degradation rather than MDM2-mediated ubiquitination. Taken together, the DpdtbA-induced growth inhibition in a mechanism was through inactivating the p53/EGFR/AKT signal pathway.

SUBMITTER: Wang Z

PROVIDER: S-EPMC6636558 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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DpdtbA-Induced Growth Inhibition in Human Esophageal Cancer Cells Involved Inactivation of the p53/EGFR/AKT Pathway.

Wang Zhuo Z Li Cuiping C Li Yongli Y Guo Xingshuang X Yan Zhaoyu Z Gao Fulian F Li Changzheng C

Oxidative medicine and cellular longevity 20190701

Esophageal cancer (ESC) is one of the most deadly diseases for human. p53 in most cancers, including ESC cell, is mutated, and the mutated p53 losses its original function and acquires "gain of function" that allows for promoting the hallmarks of cancer, such as antiapoptosis, metastasis, invasion, angiogenesis, and resistance to chemotherapy. Targeting p53 through either introducing wild-type or degrading mutated p53 is an important strategy in cancer therapy. Di-2,2'-pyridine ketone dithiocarb ...[more]

PMID: 31354907

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DpdtbA-Induced Growth Inhibition in Human Esophageal Cancer Cells Involved Inactivation of the p53/EGFR/AKT Pathway.

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DpdtbA-Induced Growth Inhibition in Human Esophageal Cancer Cells Involved Inactivation of the p53/EGFR/AKT Pathway.

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