Gap junctions sensitize cancer cells to proteasome inhibitor MG132-induced apoptosis
Tao Huang1, Ying Zhu, Xin Fang
1Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
Abstract:
Proteasome inhibition is a promising approach for cancer therapy. However, the mechanisms involved have not been fully elucidated. Gap junctions play important roles in the regulation of tumor cell phenotypes and mediation of the bystander effect in cancer therapy. Because the degradation of gap junction proteins involves the proteasome, we speculated that altered gap junctions might contribute to the antitumor activities of proteasome inhibition. Incubation of Hepa-1c1c7 cells with the proteasome inhibitor MG132 elevated the levels of gap junction protein connexin 43 (Cx43) and promoted gap junctional intercellular communication. This was associated with a marked accumulation of ubiquitylated Cx43 and a significantly decreased rate of Cx43 degradation. The elevated Cx43 contributed to MG132-induced cell apoptosis. This is shown by the observations that: (i) overexpression of Cx43 in the gap junction-deficient LLC-PK1 cells rendered them vulnerable to MG132-elicited cell injury; (ii) fibroblasts derived from Cx43-null mice were more resistant to MG-132 compared with Cx43 wild-type control; and (iii) the gap junction inhibitor flufenamic acid significantly attenuated cell damage caused by MG132 in Hepa-1c1c7 cells. Further studies demonstrated that MG132 activates endoplasmic reticulum stress. Exposure of cells to the endoplasmic reticulum stress inducers thapsigargin and tunicamycin also led to cell apoptosis, which was modulated by Cx43 levels in a way similar to MG132. These results suggested that elevated Cx43 sensitizes cells to MG132-induced cell apoptosis. Regulation of gap junctions could be an important mechanism behind the antitumor activities of proteasome inhibitors.
Insights
Proteasome inhibitors like MG132 increase gap junction protein connexin 43 (Cx43) levels, enhancing cell communication and apoptosis. This elevated Cx43 sensitizes cancer cells to proteasome inhibitor therapy.
Area of Science:
- Oncology
- Cell Biology
- Molecular Medicine
Background:
- Proteasome inhibition is a key cancer therapy strategy, but its mechanisms require further elucidation.
- Gap junctions are crucial for regulating tumor cell behavior and mediating therapeutic bystander effects.
- Proteasomal degradation impacts gap junction proteins, suggesting a link between proteasome inhibition and gap junction function.
Purpose of the Study:
- To investigate the role of altered gap junctions in the antitumor activities of proteasome inhibitors.
- To determine if proteasome inhibition affects gap junction protein levels and function.
- To explore the contribution of gap junction protein connexin 43 (Cx43) to proteasome inhibitor-induced apoptosis.
Main Methods:
- Incubation of Hepa-1c1c7 cells with the proteasome inhibitor MG132.
- Analysis of connexin 43 (Cx43) levels, ubiquitylation, and degradation.
- Assessment of gap junctional intercellular communication.
- Functional studies using Cx43-overexpressing cells, Cx43-null fibroblasts, and gap junction inhibitors.
- Investigation of endoplasmic reticulum (ER) stress induction.
Main Results:
- MG132 treatment increased Cx43 levels and gap junctional communication in Hepa-1c1c7 cells.
- Accumulation of ubiquitylated Cx43 and reduced Cx43 degradation were observed.
- Elevated Cx43 enhanced MG132-induced apoptosis, as evidenced by increased sensitivity in Cx43-overexpressing cells and resistance in Cx43-null cells.
- The gap junction inhibitor flufenamic acid reduced MG132-induced cell damage.
- MG132 induced endoplasmic reticulum stress, and Cx43 modulated ER stress-induced apoptosis similarly to MG132.
Conclusions:
- Elevated Cx43 sensitizes cells to proteasome inhibitor-induced apoptosis.
- Regulation of gap junctions is a significant mechanism underlying the antitumor effects of proteasome inhibitors.
- Targeting gap junctions could enhance proteasome inhibitor efficacy in cancer therapy.
Related Concept Videos
01:31The Intrinsic Apoptotic Pathway
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
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...
01:17The Extrinsic Apoptotic Pathway
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...