Inhibition of Galectin-1 Sensitizes HRAS-driven Tumor Growth to Rapamycin Treatment

Michael, James V.; Wurtzel, Jeremy G. T.; Goldfinger, Lawrence E.

doi:10.21873/anticanres.11074

Cited by 18 publications

(21 citation statements)

References 19 publications

(30 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IHC analysis of resected tumors indicated a marked reduction in pS6 in rapamycintreated HRAS tumors, but also in untreated HRAS-tR tumors. Interestingly, pERK was also reduced in HRAS tumors with rapamycin (173). Together, our recent results indicate that genetically enforced lipid ordered domain sequestration inhibits HRAS-induced mTORC1 signaling, and sensitizes HRAS tumors to rapamycin treatment.…”

Section: Hras-induced Tumor Growth Regulated By Plasma Membrane Microsupporting

confidence: 68%

“…These profound results indicate that combined mTOR/Gal-1 inhibition yields stasis of HRAS-driven tumor growth. Thus, inhibition of Gal-1 results in a blockade of GTP-HRAS shuttling from the lipid ordered domain and inhibition of MAPK signaling, and sensitizes tumors driven by CA HRAS to mTOR inhibition ( Figure 9A) (173). Inhibition of Gal-1 using OTX008 is currently under clinical evaluation, and our findings support the development of Gal-1 targeting schemes to limit progression of mutant HRAS cancers.…”

Section: Gal-1 and Combinatorial Inhibitionsupporting

confidence: 64%

See 1 more Smart Citation

Regulation of Ras signaling and function by plasma membrane microdomains

Goldfinger

Michael

2017

BST

View full text Add to dashboard Cite

Section: Hras-induced Tumor Growth Regulated By Plasma Membrane Microsupporting

confidence: 68%

Section: Gal-1 and Combinatorial Inhibitionsupporting

confidence: 64%

Regulation of Ras signaling and function by plasma membrane microdomains

Goldfinger

Michael

2017

BST

View full text Add to dashboard Cite

“…The activation of HRas is likewise associated with galectin-1. The inhibitors of galectin-1, including OTX008, and of mTOR, including rapamycin, may nearly completely suppress Hras-mutant cancers (48). A recent study has revealed that HRas mutations have the tendency to affect patients' outcomes (hazard ratio = 0.545, 95% confidence interval = 0.277-1.073, P= 0.079) (49).…”

Section: Discussionmentioning

confidence: 99%

Delineating the underlying molecular mechanisms and key genes involved in metastasis of colorectal cancer via bioinformatics analysis

Chen

Zhou

et al. 2018

Oncol Rep

View full text Add to dashboard Cite

Colorectal cancer (CRC) is considered the world's fourth most deadly cancer. Its metastasis is associated with poor prognosis and weakens the effects of treatment. However, the potential molecular mechanisms and key genes involved in CRC metastasis have remained to be comprehensively elucidated. The objective of the present study was to identify the key genes and molecular pathways underlying CRC metastasis. Differentially expressed genes (DEGs) between primary CRC tissues and metastatic CRC were identified by analyzing the GSE2509 dataset from the Gene Expression Omnibus database. Subsequently, the DEGs were subjected to Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analyses via the Database for Annotation, Visualization and Integrated Discovery (DAVID). Next, the top ten hub genes were identified in a protein-protein interaction (PPI) network. Sub-network and pathway enrichment analysis were respectively performed with the plugin MCODE and DAVID. Finally, reverse transcription-quantitative polymerase chain reaction assays were performed to corroborate the expression levels of the top five potential metastasis-associated genes in the clinical samples of CRC patients. A total of 7,384 DEGs were obtained, among which 3,949 were upregulated and 3,435 were downregulated. GO and KEGG enrichment analyses identified numerous possible biological processes and pathways that may have a role in the metastasis of CRC. The leading ten hub genes, recognized from the PPI, were epidermal growth factor receptor (EGFR), Has proto-oncogene GTPase (HRas), Wnt family member 5A (Wnt5a), serine/threonine kinase 1 (Akt1), cyclin-dependent kinase inhibitor 1A (CDKN1a), early growth response 1, Ras homolog family member A, cyclin D1 and Ras-related C3 botulinum toxin substrate 1. Sub-network analysis disclosed the most prominent three modules. Ultimately, EGFR, HRas and Akt1 were verified to be upregulated DEGs, while Wnt5a and CDKN1a were downregulated DEGs when compared with the primary controls. In conclusion, the present study revealed several key genes and relevant molecular mechanisms that may enhance the current understanding of CRC metastasis, making them significant potential foci for the discovery of further CRC treatments.

show abstract

“…This may require novel inhibitors against Gal-1 that interfere with its activity to complex in particular with the Raf effectors; an interaction which is required for its nanocluster promoting activity [ 19 ]. Interestingly, the Gal-1 inhibitor OTX008, which is not a classical carbohydrate binding region competitor, was recently shown to synergize with rapamycin to block tumor growth [ 36 ]. Intriguingly, an OTX008 related compound binds at a Gal-1 site that may allosterically affect its binding to Raf-effectors or Gal-1 dimerization and hence its nanocluster scaffolding activity [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner

et al. 2017

View full text Add to dashboard Cite

Currently several combination treatments of mTor- and Ras-pathway inhibitors are being tested in cancer therapy. While multiple feedback loops render these central signaling pathways robust, they complicate drug targeting.Here, we describe a novel H-ras specific feedback, which leads to an inadvertent rapalog induced activation of tumorigenicity in Ras transformed cells. We find that rapalogs specifically increase nanoscale clustering (nanoclustering) of oncogenic H-ras but not K-ras on the plasma membrane. This increases H-ras signaling output, promotes mammosphere numbers in a H-ras-dependent manner and tumor growth in ovo. Surprisingly, also other FKBP12 binders, but not mTor-inhibitors, robustly decrease FKBP12 levels after prolonged (>2 days) exposure. This leads to an upregulation of the nanocluster scaffold galectin-1 (Gal-1), which is responsible for the rapamycin-induced increase in H-ras nanoclustering and signaling output. We provide evidence that Gal-1 promotes stemness features in tumorigenic cells. Therefore, it may be necessary to block inadvertent induction of stemness traits in H-ras transformed cells by specific Gal-1 inhibitors that abrogate its effect on H-ras nanocluster. On a more general level, our findings may add an important mechanistic explanation to the pleiotropic physiological effects that are observed with rapalogs.

show abstract

Inhibition of Galectin-1 Sensitizes HRAS-driven Tumor Growth to Rapamycin Treatment

Cited by 18 publications

References 19 publications

Regulation of Ras signaling and function by plasma membrane microdomains

Regulation of Ras signaling and function by plasma membrane microdomains

Delineating the underlying molecular mechanisms and key genes involved in metastasis of colorectal cancer via bioinformatics analysis

Rapalogs can promote cancer cell stemness in vitro in a Galectin-1 and H-ras-dependent manner

Contact Info

Product

Resources

About