Richard Anderson Lab

Research: Translational Applications to Human Diseases

Cytosolic signalng pathways

In the News

UW-Madison scientists find how many cancers may evade treatment

UW-Madison News, Jan. 15, 2015
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“We predict it could be an incredibly effective way of treating cancers,” says Anderson, who notes both types of drugs already exist and have FDA approval. “It could have potentially a very rapid impact on cancer treatment.”

PIPKIγ is highly expressed in triple negative breast cancers and expression correlates with poor disease prognosis(Breast Cancer Res., 12(1):R6). Emerging evidence indicates that in triple negative breast cancers there appears to be a switch in the expression of PIPKIγi1-5 isoforms, where PIPKIγi1 and PIPKIγi2 increase (pro-migration/invasion) with a loss of PIPKIγi5 (increased EGFR signaling) and PIPKIγi4 (loss nuclear signaling and PTEN expression). We plan to determine if such a switch may also occur in head and neck, small cell lung, colon, pancreatic, gliomas and other cancers. This PIPKIγ switch has significant therapeutic implications, as the role of PIPKIγi5 and pathway components in endosomal sorting of EGF receptor has strong implications in EGFR regulated cancers with potential roles in resistance to multiple therapies. LAPTM4B appears to be key oncogene that regulates EGFR signaling. LAPTM4B is regulated by both PI4,5P2 and PIPKIγi5 binding that block LAPTM4B regulation of EGFR. A drug that would block LAPTM4B inhibition of EGFR downregulation may have theraputic potential.

 

IQGAP1 has known roles in cancer progression and metastasis (see discussion, EMBO J. 32, 2617-30). The roles of IQGAP1 in cell migration, invasion and cell proliferation are controlled by the recruitement of specific signaling enzymes to the IQGAP1 complex. For IQGAP1’s role in migration, invasion and cell proliferation this requires interactions with PI 3-kinase and PIP kinases. These interactions occur within defined IQGAP1 domains and are inhibited by short peptides that specifically block the PI 3-kinase and PIP kinase binding to IQGAP1. This indicates that peptides or small molecules that block PI 3-kinase and PIP kinase binding to IQGAP1 could be a theraputic approach to block metastasis and progression of some cancers. This approach has been validated for IQGAP1 control of the MAP kinase pathway which also requires interaction of MAP kinase components with IQGAP1.

Gene expression, signaling and nuclear organization

Star-PAP controls PTEN, Mdm2, AKT1-3, NQO1, and human papillomavirus E6/E7 expression. These genes control p53 function, apoptosis, cell proliferation and cancer progression. The expression of these genes is controlled by DNA damage, oxidative stress, and growth factor signaling pathways that regulate Star-PAP 3’-end processing. We have shown that inhibition of Star-PAP modulates p53 and sensitizes cells to VP-16(Oncogene doi:10.1038/onc.2013.14), indicating that Star-PAP is a putative anti-cancer therapeutic target. Defining Star-PAP’s role in controlling expression of oncogenes and tumor suppressors is likely to identify drug targets that could control the expression of these genes.

 

The nuclear architecture is dramatically altered in cancer cells and these changes likely impact gene expression and mRNA processing. Phosphoinositide lipid messengers largely function as spatial signaling molecules that organize cellular architecture. As such, there is a potential role for nuclear PIP kinases and PI4,5P2 generation in the spatial organization of gene expression and mRNA processing. A key example is control of PTEN expression by Star-PAP that is regulated by PI4,5P2. Changes in nuclear organization have the potential to spatially disconnect PI4,5P2 synthesis from regions of PTEN expression, this could block Star-PAP processing of the PTEN mRNA resulting in loss of PTEN and enhanced proliferation of cancer cells.