{"id":10940,"date":"2016-12-19T08:51:40","date_gmt":"2016-12-19T08:51:40","guid":{"rendered":"http:\/\/revoscience.com\/en\/?p=10940"},"modified":"2016-12-19T08:51:40","modified_gmt":"2016-12-19T08:51:40","slug":"cancer-signaling-pathway-illuminate-new-avenue-therapy","status":"publish","type":"post","link":"https:\/\/www.revoscience.com\/en\/cancer-signaling-pathway-illuminate-new-avenue-therapy\/","title":{"rendered":"Cancer signaling pathway could illuminate new avenue to therapy"},"content":{"rendered":"
\"Suyong
Suyong Choi<\/figcaption><\/figure>\n

Researchers from the\u00a0University of Wisconsin\u00a0School of Medicine and Public Health<\/a>\u00a0and\u00a0Carbone Cancer Center<\/a>\u00a0have better defined\u00a0a pro-growth signaling pathway common to many\u00a0cancers\u00a0that, when blocked,\u00a0kills cancer cells but leaves healthy cells\u00a0comparatively\u00a0unharmed.<\/span><\/p>\n

The study, published Nov. 21 \u00a0in the journal\u00a0Nature Cell Biology<\/em><\/a>,\u00a0could establish new avenues of\u00a0therapeutic treatments for\u00a0many\u00a0types of solid tumors.<\/span><\/p>\n

Growth signals typically come in the form of\u00a0chemical\u00a0agonists outside of\u00a0cells\u00a0that bind to\u00a0protein receptors\u00a0on cells. Activated receptors\u00a0are responsible for transmitting the signal to the inside of the cell, ultimately generating a growth messenger called PIP3.\u00a0Two years ago,\u00a0research out of UW\u2013Madison Professor\u00a0Richard Anderson<\/a>\u2019s lab found that\u00a0some\u00a0of these agonist-stimulated receptors\u00a0continue to transmit the signal<\/a>\u00a0even after they\u00a0have been\u00a0pulled into the cell,\u00a0sequestered\u00a0in\u00a0vesicles\u00a0called endosomes\u00a0and\u00a0presumably on their way to being degraded.<\/span><\/p>\n

\u201cAccording to dogma in the literature,\u00a0receptors shouldn\u2019t\u00a0make PIP3 at these\u00a0internal\u00a0sites, but they were,\u201d Anderson says. \u201cWe set out to ask,\u00a0\u2018Why is that?\u2019\u201d<\/span><\/p>\n

In\u00a0this new study,\u00a0a\u00a0postdoctoral fellow in Anderson\u2019s lab, Suyong Choi, showed that\u00a0the proteins known to be in this signal\u00a0transmission cascade were all\u00a0present on endosomes inside the cell,\u00a0supporting\u00a0the idea that the\u00a0key growth message was being signaled\u00a0from\u00a0these internal compartments. However, there was one fact which they\u00a0could not biologically explain:\u00a0In a typical signaling cascade, each step amplifies the signal, suggesting there should be more and more of the messenger\u00a0molecules;\u00a0but\u00a0here,\u00a0levels of\u00a0PIP3\u00a0and other intermediary messengers\u00a0were\u00a0too low to\u00a0be detected in endosomes.<\/span><\/p>\n

\u201cA scaffold completely solves this issue, because it\u00a0acts like an assembly line, bringing together all of\u00a0the proteins and passing one messenger molecule to the next protein in the cascade\u00a0until the last protein, PI3K, is activated\u00a0and generates\u00a0PIP3,\u201d\u00a0Anderson says. \u201cSuyong\u00a0Choi\u00a0found that the scaffolding protein IQGAP1 brings\u00a0all of\u00a0these proteins together\u00a0like a happy family\u00a0on\u00a0the endosome. It\u2019s an incredibly efficient mechanism.\u201d<\/span><\/p>\n

Choi discovered\u00a0that the IQGAP1 complex pulls together all of the\u00a0signaling components in the\u00a0PI3K\u00a0pathway. Remarkably,\u00a0this assembly happens\u00a0in response to nearly\u00a0all agonists\u00a0that switch on growth and\u00a0cell survival signals in cells.\u00a0Once Choi had established\u00a0how\u00a0the proteins in the complex interacted,\u00a0he was able to block scaffold formation in cells\u00a0by adding a small, competing fragment of the IQGAP1 protein.<\/span><\/p>\n

\"Richard
Richard Anderson<\/figcaption><\/figure>\n

\u201cIt worked beautifully to\u00a0block assembly of\u00a0IQGAP1\u00a0and PI3K complex,\u201d Anderson says.\u00a0\u201cThe really cool thing was,\u00a0when we treated\u00a0different cells\u00a0with these\u00a0inhibitory fragments, the disruption of\u00a0IQGAP1 and PI3K complex formation\u00a0had almost no effect on\u00a0normal cells\u00a0but it killed cancer cells very efficiently.\u201d<\/span><\/p>\n

PI3K is an essential\u00a0protein, and cells (and whole organisms) die if\u00a0they\u00a0do not have any functional PI3K\u00a0because the\u00a0protein is involved in multiple signaling pathways. However, it is specifically this\u00a0pathway, mediated through IQGAP1,\u00a0that\u00a0is\u00a0required\u00a0for\u00a0the\u00a0growth and\u00a0survival of cancer cells but not normal\u00a0cells.\u00a0In fact, mice lacking IQGAP1 develop normally but are resistant to\u00a0developing\u00a0solid tumors.<\/span><\/p>\n

\u201cPharmaceutical companies have developed PI3K inhibitors, but many of these have failed, likely because they\u2019re hitting all PI3Ks and the different pathways,\u201d Anderson said.\u00a0\u201cIf you can specifically disrupt this agonist-activated PI3K pathway, the one that has a specific role in cancer,\u00a0then\u00a0you can\u00a0effectively treat cancers. We think that\u2019s what this study is showing.\u201d<\/span><\/p>\n

The researchers further showed that this same scaffolding was used to transmit insulin signaling, suggesting the pathway\u00a0may play a role in the onset of diabetes and cardiovascular diseases\u00a0as well as cancers.<\/span><\/p>\n

This work\u00a0was supported by grants from the National Institutes of Health and the American Heart Association. The\u00a0Wisconsin Alumni Research Foundation is developing a patent on the methods and early compounds that block this pathway.<\/span><\/p>\n

 <\/p>\n","protected":false},"excerpt":{"rendered":"

Growth signals typically come in the form of chemical agonists outside of cells that bind to protein receptors on cells. Activated receptors are responsible for transmitting the signal to the inside of the cell, ultimately generating a growth messenger called PIP3. Two years ago, research out of UW\u2013Madison Professor Richard Anderson\u2019s lab found that some of these agonist-stimulated receptors continue to transmit the signal even after they have been pulled into the cell, sequestered in vesicles called endosomes and presumably on their way to being degraded.<\/p>\n","protected":false},"author":6,"featured_media":10769,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[26,17],"tags":[],"class_list":["post-10940","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-medicine","category-research"],"featured_image_urls":{"full":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/12\/UW-Madision-logo.jpg",736,495,false],"thumbnail":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/12\/UW-Madision-logo-150x150.jpg",150,150,true],"medium":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/12\/UW-Madision-logo-300x202.jpg",300,202,true],"medium_large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/12\/UW-Madision-logo.jpg",736,495,false],"large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/12\/UW-Madision-logo.jpg",736,495,false],"1536x1536":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/12\/UW-Madision-logo.jpg",736,495,false],"2048x2048":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/12\/UW-Madision-logo.jpg",736,495,false],"ultp_layout_landscape_large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/12\/UW-Madision-logo.jpg",736,495,false],"ultp_layout_landscape":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/12\/UW-Madision-logo.jpg",736,495,false],"ultp_layout_portrait":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/12\/UW-Madision-logo.jpg",600,404,false],"ultp_layout_square":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/12\/UW-Madision-logo.jpg",600,404,false],"newspaper-x-single-post":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/12\/UW-Madision-logo.jpg",729,490,false],"newspaper-x-recent-post-big":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/12\/UW-Madision-logo.jpg",535,360,false],"newspaper-x-recent-post-list-image":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/12\/UW-Madision-logo.jpg",95,65,false],"web-stories-poster-portrait":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/12\/UW-Madision-logo.jpg",640,430,false],"web-stories-publisher-logo":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/12\/UW-Madision-logo.jpg",96,65,false],"web-stories-thumbnail":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/12\/UW-Madision-logo.jpg",150,101,false]},"author_info":{"info":["Amrita Tuladhar"]},"category_info":"Medicine<\/a> Research<\/a>","tag_info":"Research","comment_count":"0","_links":{"self":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts\/10940","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/users\/6"}],"replies":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/comments?post=10940"}],"version-history":[{"count":0,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts\/10940\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/media\/10769"}],"wp:attachment":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/media?parent=10940"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/categories?post=10940"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/tags?post=10940"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}