Related Experiment Video

Updated: Jan 29, 2026

Traditional Trail Making Test Modified into Brand-new Assessment Tools: Digital and Walking Trail Making Test
08:07

Traditional Trail Making Test Modified into Brand-new Assessment Tools: Digital and Walking Trail Making Test

Published on: November 23, 2019

11.8K

Targeting KPNB1 overcomes TRAIL resistance by regulating DR5, Mcl-1 and FLIP in glioblastoma cells

Zhi-Chuan Zhu1, Ji-Wei Liu2, Can Yang1,3

  • 1State Key Laboratory of Neuroscience, Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.

Cell Death & Disease
|February 12, 2019
PubMed

Insights

Inhibiting Karyopherin β1 (KPNB1) enhances cancer cell death by boosting TRAIL signaling through the unfolded protein response (UPR). This strategy overcomes TRAIL resistance, offering a new approach for cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows anticancer potential but faces resistance in many cancers.
  • Karyopherin β1 (KPNB1) inhibition was previously thought to enhance TRAIL efficacy by increasing cell surface DR5.
  • The precise mechanisms by which KPNB1 inhibition impacts TRAIL sensitivity remain incompletely understood.

Purpose of the Study:

  • To elucidate the detailed molecular mechanisms by which KPNB1 inhibition sensitizes glioblastoma cells to TRAIL-induced apoptosis.
  • To investigate the role of the unfolded protein response (UPR) in KPNB1 inhibition-mediated sensitization to TRAIL.
  • To identify novel therapeutic targets for optimizing TRAIL-based cancer treatments.

Main Methods:

  • Utilized genetic and pharmacological inhibition of KPNB1 in glioblastoma cell lines.
  • Investigated the role of the unfolded protein response (UPR) pathway, including ATF4 and 4E-BP1.
  • Assessed the expression and function of apoptosis-related proteins such as DR5, Bax, Bak, Mcl-1, FLIPs, and caspase-8.
  • Analyzed the impact of autophagy inhibition on apoptosis induction and caspase-8 stability.
  • Employed caspase-8 inhibitors to confirm the role of caspase-8 in observed apoptosis.

Main Results:

  • KPNB1 inhibition potentiated TRAIL-induced apoptosis selectively in glioblastoma cells via the UPR.
  • Enhanced DR5 expression and death-inducing signaling complex (DISC) assembly were observed.
  • KPNB1 inhibition led to the release of Bax and Bak from Mcl-1 and downregulated FLIP variants.
  • Autophagy was induced by KPNB1 inhibition, accelerating cleaved caspase-8 clearance; inhibiting autophagy flux enhanced apoptosis.
  • The pro-apoptotic effect was dependent on caspase-8 activity.

Conclusions:

  • KPNB1 inhibition sensitizes glioblastoma to TRAIL through a complex UPR-mediated mechanism involving DR5 upregulation, altered Bcl-2 family protein balance, and modulation of FLIPs.
  • Autophagy plays a dual role, and its inhibition can enhance TRAIL efficacy when combined with KPNB1 inhibition.
  • These findings reveal a novel molecular framework for improving TRAIL-directed cancer therapy.

More Related Videos

Patterning of Embryonic Stem Cells Using the Bio Flip Chip05:25

Patterning of Embryonic Stem Cells Using the Bio Flip Chip

Published on: October 1, 2007

9.9K
Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down08:59

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down

Published on: December 11, 2017

7.6K

Related Concept Videos

Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
38.5K
pH Regulation in Cells01:28

pH Regulation in Cells

pH plays a critical role in maintaining normal cellular activities. It helps maintain the structure and function of various proteins, dictates the charge on cellular membranes, and is crucial for metabolic reactions inside the cell. Moreover, cells use the energy from the proton motive force to generate ATP.
Cytosolic pH
Under physiological conditions, the cytosolic pH is slightly more acidic than the extracellular pH. However, cells must prevent further acidification of their cytosol to...
7.6K
Regulated Protein Degradation02:58

Regulated Protein Degradation

It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
8.8K
Regulated mRNA Transport02:22

Regulated mRNA Transport

In eukaryotes, transcription and translation are compartmentalized; an mRNA is first synthesized in the nucleus and then selectively transported to the cytoplasm for protein synthesis. Before transport, a pre-mRNA undergoes several steps of post-transcriptional modifications including splicing, 5' capping, and the addition of a poly-adenine tail. Various proteins bind to the pre-mRNA during these modifications. The mRNA transport takes place with the help of multiple proteins playing...
7.0K
Positive Regulator Molecules01:45

Positive Regulator Molecules

To consistently produce healthy cells, the cell cycle—the process that generates daughter cells—must be precisely regulated.
136.1K
Epigenetic Regulation01:46

Epigenetic Regulation

Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
33.7K