Dataset Information

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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Project description:Introduction: The clinical benefit of EGFR tyrosine kinase inhibitor (TKI) treatment in non-small cell lung cancer (NSCLC) patients with activating EGFR mutations is temporary, as virtually all patients develop acquired EGFR TKI resistance that occurs via diverse mechanisms. Here, we identified increased FGFR1 expression as such a resistance mechanism and using pathways analysis and drug combination testing we identified a novel combination treatment to control growth of these resistant tumors. Methods: Novel erlotinib-resistant NSCLC cell lines were generated and analyzed by mass spectrometry-based proteomics to identify altered pathways associated with erlotinib resistance. The altered pathways were further analyzed in gefitinib and osibenib resistant cell lines. Small molecule inhibitor combinations were used to block the altered pathways and investigate growth reduction in vitro and in two xenograft mouse models. FGFR1 mRNA levels were examined in pre- and (post?)- EGFR TKI treatment clinical tumor samples. Results: Proteomic analysis revealed increased expression of FGFR1 and AXL as well as increased Akt and ERK1/2 activation in a panel of novel erlotinib-resistant HCC827 cell lines. Combined treatment with erlotinib or osimertinib and a panel of small molecule inhibitors targeting AXL/MET, FGFRs, Akt, PI3K/mTOR, MEK or ERK1/2 showed that the most prominent re-sensitization to EGFR TKI occurred with the pan-FGFR inhibitor, PD173074. Interestingly, simultaneous blockade of components of the Akt pathway using specific Akt or dual PI3K-mTOR inhibitors combined with inhibitors targeting the FGFR family exhibited the most efficient growth inhibition of FGFR1 overexpressing EGFR TKI-resistant cell lines. Phosphorylation of proteins downstream of Akt, including PRAS40, FOXO and S6 ribosomal protein, were completely abrogated by PD173074 combined with the Akt inhibitor GSK2141795 . Combination treatment with PD173074 and an Akt inhibitor exhibited synergistic growth inhibition in vivo in two FGFR1 overexpressing NSCLC EGFR TKI-resistant animal models. Conclusion: The significant growth inhibition in vitro and in vivo observed with PD173074 combined with Akt compared to either drug alone imply that inhibition of several key targets may be beneficial in controlling erlotinib-resistant NSCLC. The complete abrogation of PRAS40, FOXO and S6 phosphorylations by PD173074 combined with an Akt inhibitor indicates that the Akt pathway is no longer active.

Dataset Information

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

Publications

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

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