Related Experiment Video
Updated: Jul 2, 2026
Prostate Organoid Cultures as Tools to Translate Genotypes and Mutational Profiles to Pharmacological Responses
Published on: October 24, 2019
Loss of PTEN function may account for reduced proliferation pathway sensitivity to LY294002 in human prostate and
Shigeru Kanda1, Hiroshi Kanetake, Yasuyoshi Miyata
1Department of Molecular Microbiology and Immunology, Division of Endothelial Cell Biology, Nagasaki University Graduate School of Biomedical Science, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan. skanda-jua@umin.net
Purpose:
Inhibition of phosphoinositide 3 (PI3)-kinase pathway is attractive for cancer treatment. To examine the role of the phosphatase and tensin homolog (PTEN) in the development of resistance to the treatment.
Methods:
We cultured human prostate cancer cells (DU145 and PC-3 cells) and bladder cancer cells (EJ-1 and UM-UC-3 cells) with a PI3-kinase inhibitor, LY294002 for more than 6 weeks and cell proliferation was studied. Activation of Akt1 and ERK was examined by immunoblotting. We introduced the wild type PTEN in UM-UC-3 cells and their proliferation along with the signaling pathways was also examined.
Results:
After 6 weeks, proliferation pathway sensitivity to LY294002 was reduced in cells expressing PTEN, but not in PTEN-null cells. PD98059, a MAPK/ERK kinase inhibitor, significantly inhibited proliferation of PTEN-expressing cells, but not PTEN-null cells. Stable PTEN expression in PTEN-null UM-UC-3 cells increased serum-induced ERK activation and sensitivity to PD98059-treatment, and reduced sensitivity to LY294002 after 6 weeks of exposure.
Conclusions:
Loss of PTEN function may protect against resistance to PI3-kinase inhibitors through an addiction to the PI3-kinase/Akt pathway.
Insights
Loss of phosphatase and tensin homolog (PTEN) function may promote resistance to phosphoinositide 3 (PI3)-kinase inhibitors in cancer cells. PTEN-expressing cells showed increased sensitivity to PI3K/Akt pathway inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- The phosphoinositide 3 (PI3)-kinase pathway is a key target for cancer treatment.
- Understanding resistance mechanisms to PI3K inhibitors is crucial for effective therapy.
Purpose of the Study:
- To investigate the role of phosphatase and tensin homolog (PTEN) in the development of resistance to PI3-kinase inhibitors.
- To examine how PTEN status affects cancer cell sensitivity to PI3K pathway inhibition.
Main Methods:
- Human prostate and bladder cancer cell lines were cultured with the PI3-kinase inhibitor LY294002 for over 6 weeks.
- Cell proliferation, Akt1 and ERK activation were assessed.
- Wild-type PTEN was introduced into PTEN-null cells to evaluate its impact on signaling and proliferation.
Main Results:
- PTEN-expressing cells showed reduced sensitivity to LY294002 compared to PTEN-null cells after 6 weeks.
- PTEN expression increased sensitivity to MAPK/ERK kinase inhibitor PD98059.
- Restoring PTEN in PTEN-null cells enhanced ERK activation and sensitivity to PD98059 while reducing sensitivity to LY294002.
Conclusions:
- Loss of PTEN function may confer resistance to PI3-kinase inhibitors.
- Cancer cells with PTEN loss might become addicted to the PI3-kinase/Akt pathway, contributing to resistance.
- PTEN status is a critical factor in predicting response to PI3K-targeted therapies.
Related Concept Videos
02:23Abnormal Proliferation
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...