Related Experiment Video
Updated: May 24, 2026
Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy
Published on: April 3, 2018
OSU-03012 suppresses GRP78/BiP expression that causes PERK-dependent increases in tumor cell killing
Laurence Booth1, Sophie C Cazanave, Hossein A Hamed
1Department of Neurosurgery, Virginia Commonwealth University, Richmond, USA.
Abstract:
We have further defined mechanism(s) by which the drug OSU-03012 (OSU) kills tumor cells. OSU lethality was suppressed by knock down of PERK and enhanced by knock down of ATF6 and IRE1α. OSU treatment suppressed expression of the chaperone, BiP/GRP78, and did so through reduced stability of the protein. Knock down of BiP/GRP78 further enhanced OSU lethality. Overexpression of BiP/GRP78 abolished OSU toxicity. Pre-treatment of cells with OSU enhanced radiosensitivity to a greater extent than concomitant or sequential drug treatment with radiation exposure. Expression of a mutant active p110 PI3K, or mutant active forms of the EGFR in GBM cells did not differentially suppress OSU killing. In contrast loss of PTEN function reduced OSU lethality, without altering AKT, p70 S6K or mTOR activity, or the drug's ability to radiosensitize GBM cells. Knock down of PTEN protected cells from OSU and radiation treatment whereas re-expression of PTEN facilitated drug lethality and radiosensitization. In a dose-dependent fashion OSU prolonged the survival of mice carrying GBM tumors and interacted with radiotherapy to further prolong survival. Collectively, our data show that reduced BiP/GRP78 levels play a key role in OSU-3012 toxicity in GBM cells, and that this drug has in vivo activity against an invasive primary human GBM isolate.
Insights
The drug OSU-03012 (OSU) kills glioblastoma (GBM) cells by reducing BiP/GRP78 protein stability. This mechanism enhances OSU
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options.
- Understanding the mechanisms of novel anti-cancer drugs like OSU-03012 is crucial for improving therapeutic strategies.
- The unfolded protein response (UPR) pathway, involving PERK, ATF6, and IRE1α, plays a role in cancer cell survival and drug resistance.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying the tumoricidal effects of OSU-03012 in glioblastoma.
- To investigate the role of BiP/GRP78 and the unfolded protein response in OSU-03012's efficacy.
- To evaluate the synergistic potential of OSU-03012 with radiotherapy in GBM models.
Main Methods:
- Gene knockdown using siRNA targeting PERK, ATF6, IRE1α, and BiP/GRP78.
- Western blot analysis to assess protein expression and stability (e.g., BiP/GRP78).
- Cell viability assays, radiosensitization studies, and in vivo efficacy studies in mouse models of GBM.
Main Results:
- OSU-03012-induced cell death was modulated by UPR components, with knockdown of PERK suppressing lethality and ATF6/IRE1α enhancing it.
- OSU-03012 reduced BiP/GRP78 protein stability, and manipulating BiP/GRP78 levels significantly impacted OSU-03012 toxicity.
- OSU-03012 enhanced radiosensitivity, particularly when administered before radiation, and demonstrated dose-dependent survival prolongation in vivo against human GBM isolates.
Conclusions:
- Reduced BiP/GRP78 levels are a key determinant of OSU-03012's toxicity in glioblastoma cells.
- OSU-03012 exhibits significant in vivo anti-tumor activity against invasive primary human GBM.
- OSU-03012 holds promise as a therapeutic agent for glioblastoma, potentially in combination with radiotherapy.
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...
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
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...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
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...