Invariant Differential Expression Analysis Reveals Mechanism of Cancer Resistance to Cell Cycle Inhibitors
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE156657 | GEO | 2020/12/31
REPOSITORIES: GEO
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Project description:The retinoblastoma cell cycle regulator pRb and the two related proteins p107 and p130 are thought to suppress cancer development both by inhibiting the G1/S transition of the cell cycle in response to growth-arrest signals and by promoting cellular differentiation. Here, we investigated the phenotype of Rb family triple knock-out (TKO) embryonic stem cells as they differentiate in vivo and in culture. Confirming the central role of the Rb gene family in cell cycle progression, TKO mouse embryos did not survive past mid-gestation and differentiating TKO cells displayed increased proliferation and cell death. However, patterning and cell fate determination were largely unaffected in these TKO embryos. Furthermore, a number of TKO cells, including in the neural lineage, were able to exit the cell cycle in G1 and terminally differentiate. This ability of Rb family TKO cells to undergo cell cycle arrest was associated with the repression of target genes for the E2F6 transcription factor, uncovering a pRb-independent control of the G1/S transition of the cell cycle. These results show that the Rb gene family is required for proper embryonic development but is not absolutely essential to induce G1 arrest and differentiation in certain lineages. Experiment Overall Design: Genome-wide gene expression was analyzed for wild-type and TKO ESC and EB cells. Three biological replicates were isolated for wild-type ESCs, TKO ESCs, and wild-type EBs, while five biological replicates were isolated for TKO EBs.
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Project description:Zhu2015 - Combined gemcitabine and birinapant
in pancreatic cancer cells - basic PD model
Mathematical model to illustrate the
effectiveness of combination chemotherapy involving gemcitabine and
birinapant against pancreatic cancer.
This model is described in the article:
Mechanism-based mathematical
modeling of combined gemcitabine and birinapant in pancreatic
cancer cells.
Zhu X, Straubinger RM, Jusko
WJ.
J Pharmacokinet Pharmacodyn 2015 Oct;
42(5): 477-496
Abstract:
Combination chemotherapy is standard treatment for
pancreatic cancer. However, current drugs lack efficacy for
most patients, and selection and evaluation of new combination
regimens is empirical and time-consuming. The efficacy of
gemcitabine, a standard-of-care agent, combined with
birinapant, a pro-apoptotic antagonist of Inhibitor of
Apoptosis Proteins (IAPs), was investigated in pancreatic
cancer cells. PANC-1 cells were treated with vehicle,
gemcitabine (6, 10, 20 nM), birinapant (50, 200, 500 nM), and
combinations of the two drugs. Temporal changes in cell
numbers, cell cycle distribution, and apoptosis were measured.
A basic pharmacodynamic (PD) model based on cell numbers, and a
mechanism-based PD model integrating all measurements, were
developed. The basic PD model indicated that synergistic
effects occurred in both cell proliferation and death
processes. The mechanism-based model captured key features of
drug action: temporary cell cycle arrest in S phase induced by
gemcitabine alone, apoptosis induced by birinapant alone, and
prolonged cell cycle arrest and enhanced apoptosis induced by
the combination. A drug interaction term Ψ was employed in
the models to signify interactions of the combination when data
were limited. When more experimental information was utilized,
Ψ values approaching 1 indicated that specific mechanisms
of interactions were captured better. PD modeling identified
the potential benefit of combining gemcitabine and birinapant,
and characterized the key interaction pathways. An optimal
treatment schedule of pretreatment with gemcitabine for 24-48 h
was suggested based on model predictions and was verified
experimentally. This approach provides a generalizable modeling
platform for exploring combinations of cytostatic and cytotoxic
agents in cancer cell culture studies.
This model is hosted on
BioModels Database
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BIOMD0000000668.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
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2018-02-05 | BIOMD0000000668 | BioModels