Small-molecule targeting of GPCR-independent noncanonical G-protein signaling in cancer
Jingyi Zhao1, Vincent DiGiacomo1, Mariola Ferreras-Gutierrez2
1Department of Biochemistry & Cell Biology, Boston University, Chobanian & Avedisian School of Medicine, Boston, MA 02118.
Abstract:
Activation of heterotrimeric G-proteins (Gαβγ) by G-protein-coupled receptors (GPCRs) is a quintessential mechanism of cell signaling widely targeted by clinically approved drugs. However, it has become evident that heterotrimeric G-proteins can also be activated via GPCR-independent mechanisms that remain untapped as pharmacological targets. GIV/Girdin has emerged as a prototypical non-GPCR activator of G proteins that promotes cancer metastasis. Here, we introduce IGGi-11, a first-in-class small-molecule inhibitor of noncanonical activation of heterotrimeric G-protein signaling. IGGi-11 binding to G-protein α-subunits (Gαi) specifically disrupted their engagement with GIV/Girdin, thereby blocking noncanonical G-protein signaling in tumor cells and inhibiting proinvasive traits of metastatic cancer cells. In contrast, IGGi-11 did not interfere with canonical G-protein signaling mechanisms triggered by GPCRs. By revealing that small molecules can selectively disable noncanonical mechanisms of G-protein activation dysregulated in disease, these findings warrant the exploration of therapeutic modalities in G-protein signaling that go beyond targeting GPCRs.
Insights
A novel small molecule, IGGi-11, selectively inhibits non-GPCR G-protein activation, blocking cancer metastasis without affecting normal cell signaling pathways. This opens new therapeutic avenues beyond traditional drug targets.
Area of Science:
- Cellular signaling pathways
- Molecular pharmacology
- Cancer biology
Background:
- Heterotrimeric G-proteins (Gαβγ) are crucial for cell signaling, typically activated by G-protein-coupled receptors (GPCRs).
- GPCR-independent, noncanonical G-protein activation pathways exist and are implicated in diseases like cancer metastasis.
- GIV/Girdin is a known non-GPCR activator of G proteins that promotes cancer cell invasion.
Purpose of the Study:
- To introduce IGGi-11, a first-in-class small-molecule inhibitor targeting noncanonical G-protein activation.
- To investigate the selective inhibition of GIV/Girdin-mediated G-protein signaling by IGGi-11.
- To assess the efficacy of IGGi-11 in blocking cancer cell metastasis.
Main Methods:
- Development and application of IGGi-11, a small-molecule inhibitor.
- Biochemical assays to assess G-protein α-subunit (Gαi) engagement with GIV/Girdin.
- Cell-based assays to evaluate the impact on tumor cell invasion and metastatic traits.
- Comparative analysis of IGGi-11's effect on canonical (GPCR-mediated) versus noncanonical G-protein signaling.
Main Results:
- IGGi-11 specifically binds to Gαi subunits, disrupting their interaction with GIV/Girdin.
- The inhibitor effectively blocks noncanonical G-protein signaling in cancer cells.
- IGGi-11 treatment inhibits proinvasive characteristics of metastatic cancer cells.
- Canonical G-protein signaling pathways activated by GPCRs remain unaffected by IGGi-11.
Conclusions:
- Small molecules can selectively target and inhibit noncanonical G-protein activation mechanisms.
- IGGi-11 represents a promising therapeutic lead for targeting cancer metastasis via noncanonical G-protein pathways.
- These findings support the exploration of novel therapeutic strategies for G-protein-related diseases that extend beyond GPCRs.
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