Understanding the Mechanism of Cell Death in Gemcitabine Resistant Pancreatic Ductal Adenocarcinoma: A Systems Biology Approach

Abstract

Background: Gemcitabine is the standard chemotherapeutic drug administered in advanced Pancreatic Ductal Adenocarcinoma (PDAC). However, due to drug resistance in PDAC patients, this treatment has become less effective. Over the years, clinical trials for the quest of finding novel compounds that can be used in combination with gemcitabine have met very little success.

Objective: To predict the driving factors behind pancreatic ductal adenocarcinoma, and to understand the effect of these components in the progression of the disease and their contribution to cell growth and proliferation.

Methods: With the help of systems biology approaches and using gene expression data, which is generally found in abundance, dysregulated elements in key signalling pathways were predicted. Prominent dysregulated elements were integrated into a model to simulate and study the effect of gemcitabine-induced hypoxia.

Results: In this study, several transcription factors in the form of key drivers of cancer-related genes were predicted with the help of CARNIVAL, and the effect of gemcitabine-induced hypoxia on the apoptosis pathway was shown to have an effect on the downstream elements of two primary pathway models; EGF/VEGF and TNF signalling pathway.

Conclusion: It was observed that EGF/VEGF signalling pathway played a major role in inducing drug resistance through cell growth, proliferation, and avoiding cell death. Targeting the major upstream components of this pathway could potentially lead to successful treatment.

Keywords: PDAC; apoptosis; cell death; cell signalling; gemcitabine; hypoxia; systems biology.

Fig. (1)

Network for PANC-1 cell line treated with 100nm gemcitabine inferred from CARNIVAL. Upregulated components are depicted in blue, while downregulated ones are represented in red. Black edges represent the activating function, while red edges represent the inhibiting function. Nodes with a double circle represent transcription factors. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (2)

A model for gemcitabine apoptosis pathway. A) Major signaling pathways initiated by TNF, VEGFA, and EGF are represented in this model. Intrinsic and extrinsic apoptotic pathways were integrated from the literature. B) Activity level of proteins was simulated for 240 minutes and the resulting plot was generated, where green indicates maximum activity and red indicates minimum activity. C) The description of each node used in the model is described. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (3)

A) A model depicting the regulation of apoptosis through the TNF pathway and B) Simulation of the signaling process. Exhaustion of TNF results in the deactivation of IKK, which prevents NF-κB from continuing the oscillation cycle. In its inhibited state, NF-κB is unable to regulate XIAP, thus halting the inhibition of CAS9 and CAS3. The increasing CAS3 signal indicates cell death. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (4)

A) and B) depict the model for signal transduction through EGF/VEGF pathway under the influence of hypoxia. Due to the constant influence of HIF1 on VEGFA, the components downstream of KDR are constantly in an active state. Due to this, IKK helps NF-κB to remain in its switched-on state, effectively preventing apoptosis. By disabling the hypoxia node in C) and D), the normal functioning of the components can be seen, along with an increase in the CAS3 level. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (5)

A visual summary of the conclusion. (A higher resolution / colour version of this figure is available in the electronic copy of the article).