Caveolin-1 suppresses tumor formation through the inhibition of the unfolded protein response
María I Díaz1,2, Paula Díaz1,2,3, Jimena Castillo Bennett1,2,3
1Laboratory of Cellular Communication, Center for studies on Exercise, Metabolism and Cancer (CEMC), Faculty of Medicine, University of Chile, Santiago, Chile.
Abstract:
Caveolin-1 (CAV1), is a broadly expressed, membrane-associated scaffolding protein that acts both, as a tumor suppressor and a promoter of metastasis, depending on the type of cancer and stage. CAV1 is downregulated in human tumors, tumor cell lines and oncogene-transformed cells. The tumor suppressor activity of CAV1 is generally associated with its presence at the plasma membrane, where it participates, together with cavins, in the formation of caveolae and also has been suggested to interact with and inhibit a wide variety of proteins through interactions mediated by the scaffolding domain. However, a pool of CAV1 is also located at the endoplasmic reticulum (ER), modulating the secretory pathway in a manner dependent on serine-80 (S80) phosphorylation. In melanoma cells, CAV1 expression suppresses tumor formation, but the protein is largely absent from the plasma membrane and does not form caveolae. Perturbations to the function of the ER are emerging as a central driver of cancer, highlighting the activation of the unfolded protein response (UPR), a central pathway involved in stress mitigation. Here we provide evidence indicating that the expression of CAV1 represses the activation of the UPR in vitro and in solid tumors, reflected in the attenuation of PERK and IRE1α signaling. These effects correlated with increased susceptibility of cells to ER stress and hypoxia. Interestingly, the tumor suppressor activity of CAV1 was abrogated by site-directed mutagenesis of S80, correlating with a reduced ability to repress the UPR. We conclude that the tumor suppression by CAV1 involves the attenuation of the UPR, and identified S80 as essential in this context. This suggests that intracellular CAV1 regulates cancer through alternative signaling outputs.
Insights
Caveolin-1 (CAV1) suppresses tumors by repressing the unfolded protein response (UPR). Its tumor suppressor activity relies on serine-80 phosphorylation, highlighting intracellular CAV1
Area of Science:
- Cell Biology
- Cancer Biology
- Molecular Oncology
Background:
- Caveolin-1 (CAV1) is a scaffolding protein with dual roles in cancer, acting as both a tumor suppressor and a promoter of metastasis.
- CAV1 is often downregulated in tumors, and its tumor-suppressive functions are linked to plasma membrane localization and caveolae formation.
- Intracellular CAV1, particularly at the endoplasmic reticulum (ER), influences the secretory pathway and is implicated in cancer progression.
Purpose of the Study:
- To investigate the role of intracellular Caveolin-1 (CAV1) in regulating the unfolded protein response (UPR) and its impact on tumor suppression.
- To determine if CAV1's tumor suppressor activity is associated with its modulation of ER stress pathways.
- To elucidate the significance of serine-80 (S80) phosphorylation in CAV1's function within the context of cancer and ER stress.
Main Methods:
- In vitro and in vivo studies using cancer cell lines and solid tumors.
- Analysis of CAV1 expression levels and localization (plasma membrane vs. ER).
- Assessment of unfolded protein response (UPR) activation, including PERK and IRE1α signaling pathways.
- Site-directed mutagenesis of serine-80 (S80) in CAV1 to evaluate its functional importance.
Main Results:
- CAV1 expression was found to repress the activation of the unfolded protein response (UPR) in both in vitro and solid tumor settings.
- CAV1-mediated repression of UPR correlated with reduced PERK and IRE1α signaling.
- Cells expressing CAV1 showed increased susceptibility to ER stress and hypoxia.
- Mutagenesis of S80 in CAV1 abrogated its tumor suppressor activity and its ability to repress the UPR.
- Intracellular CAV1, independent of caveolae formation, plays a significant role in tumor suppression.
Conclusions:
- Tumor suppression by Caveolin-1 (CAV1) is mediated through the attenuation of the unfolded protein response (UPR).
- Phosphorylation at serine-80 (S80) is critical for CAV1's ability to repress the UPR and exert its tumor suppressor effects.
- Intracellular CAV1 regulates cancer progression via alternative signaling pathways, distinct from its canonical roles at the plasma membrane.
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