Date of Award

2022-05-01

Degree Name

Doctor of Philosophy

Department

Biological Sciences

Advisor(s)

Taslim A. Al-Hilal

Second Advisor

Jianying Zhang

Abstract

Oridonin has attracted extensive attention from cancer biologists ascribed to its outstanding anticancer ability. It is a kaurane diterpene, the first bioactive natural compound from Rabdosia rubescens (Hemsl.) Hara, a natural herb. Oridonin is conventionally used as an anti-tumor, ani-inflammatory, antioxidant, and anti-bacterial compound as well as an adjunct treatment for many cancers, especially gastrointestinal tumors, such as esophageal and liver cancers. Its antitumor effects have been connected to its interference with several pathways involved in apoptosis, cell cycle arrest, cell proliferation, autophagy, and cell migration. Presently, both the molecular chaperone Hsp70 and Nucleolin have been identified as targets interacting with this compound. Moreover, it is reported that oridonin can target multiple drug-resistance tumor cells. Although the efficacy of oridonin is being assessed in clinical trials, the molecular mechanism of action underlying its cellular activity is not completely understood.Esophageal cancer is the seventh most common cancer globally and ranks at the sixth of cancer-related death in 2021. The two most common histologic subtypes of esophageal cancer are esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Esophageal cancer leading to death is approximately one in every 18 cancer deaths. Among esophageal leading cancer death, 80% are due to ESCC. Esophageal carcinoma has a dire prognosis with an overall 5-year survival rate of 19%. Approximately 70% of incidence cases occur in men and esophageal cancer has the highest rates in eastern Asia. Resistant to chemotherapy is a major reason among those related to the failure of ESCC treatment. In the molecular pathogenesis aspect, many genetic mutations identified in ESCC are correlated with particular cellular pathways, such as apoptosis, growth factor receptor, DNA repair mechanisms, and cell cycle. In the present study, using a mass spectrometry-based proteomic approach, we propose to demonstrate the anti-tumor bioactivity of oridonin on ESCC at its cellular mechanism level. Below are three specific aims. 1. To verify the anticancer ability of oridonin on esophageal squamous cell carcinoma cell lines. The rationale is the compound's effect on proliferation and inhibition, and colony formation of cancer cell lines can give the initial decision of toxicity of the compound on cancer cell lines. Flow cytometry will give further information on the cell cycle or apoptosis disturbed by the compound. 2. To identify proteins involved in the anticancer activities of oridonin in esophageal cancer cell lines using a proteomics approach. This will be achieved by finding the differential expression protein spots of esophageal cancer cell lines treated with compound compared with untreated cell lines through 2-dimensional electrophoresis gels. Then we will analyze the differential expression proteins by the mass spectrometry method. 3. To explore and confirm the proteins or pathways involved in the mechanism of action of oridonin. Functional analysis of differentially expressed proteins will be performed by R software through the "clusterProfiler" package. Immunoblotting detection may help to confirm and characterize proteins involved in identified proteins/pathways.

Language

en

Provenance

Received from ProQuest

File Size

96 p.

File Format

application/pdf

Rights Holder

Xiaojun Zhang

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Biology Commons

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