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U.K. researchers slow pancreatic cancer growth by blocking key enzyme
LONDON, U.K.—A study by the Imperial College London, funded by the U.K. research charity Pancreatic Cancer Research Fund, examined the role of Hedgehog, whose usual job is to send signals to cells in embryos to divide and grow into the correct body parts. But while Hedgehog usually switches off when the embryo is formed, in many cancers, including pancreatic, it becomes abnormally reactivated.
Hedgehog cannot function without the help of the Hhat enzyme, which attaches a fatty molecule to its surface, enabling it to stick to other cells and start sending messages. In cancer, Hedgehog influences nearby healthy cells in an intricate sequence of signals, or ‘signaling pathways’, instructing them to secrete nutrients to feed the cancer cells and create the perfect environment for them to grow and spread.
Lead researcher Professor Tony Magee says “Signaling pathways are complex. They’re like a flow diagram, with a multitude of arrows travelling along and splitting off at many points along the way, each initiating a new chain reaction of activity. Whilst you could potentially stop the Hedgehog signal at many points along its journey, we wanted to see if we could simply prevent the process from starting in the first place. This meant stopping Hhat from attaching the fatty molecule to Hedgehog, which is needed for the signaling.”
Using genetic techniques, the Imperial team knocked out the Hhat function in pancreatic cancer cells and, as they hoped, the cancer cells showed substantially reduced growth and ability to spread in a test-tube assay.
The findings are published in the latest issue of the journal PLOS ONE and the following abstract speaks eloquently to the complexity of the process: “Overexpression of Hedgehog family proteins contributes to the etiology of many cancers. To be highly active, Hedgehog proteins must be palmitoylated at their N-terminus by the MBOAT family multispanning membrane enzyme Hedgehog acyltransferase (Hhat). In a pancreatic ductal adenocarcinoma (PDAC) cell line PANC-1 and transfected HEK293a cells Hhat localized to the endoplasmic reticulum. siRNA knockdown showed that Hhat is required for Sonic hedgehog (Shh) palmitoylation, for its assembly into high molecular weight extracellular complexes and for functional activity. Hhat knockdown inhibited Hh autocrine and juxtacrine signaling, and inhibited PDAC cell growth and invasiveness in vitro. In addition, Hhat knockdown in a HEK293a cell line constitutively expressing Shh and A549 human non-small cell lung cancer cells inhibited their ability to signal in a juxtacrine/paracrine fashion to the reporter cell lines C3H10T1/2 and Shh-Light2. Our data identify Hhat as a key player in Hh-dependent signaling and tumour cell transformed behaviour.”
The Hedgehog signaling pathway is a good target for cancer researchers because it mainly switches back on in cancer cells and so blocking its function does not overly affect signaling in healthy cells. However, the genetic techniques used to block Hhat in the laboratory are not possible with animal models or humans. For this, the research team needs to find chemical compounds which could be developed into a new drug to replicate this effect.
Professor Magee is confident that this is possible and, with his collaborator Dr. Ed Tate, is planning to screen a huge library of molecules to select those whose properties look most likely to inhibit Hhat’s function. They will test the best candidate molecules in mice to see if they can replicate their study findings before moving on to human clinical trials.
Maggie Blanks, CEO of the Pancreatic Cancer Research Fund, said “Professor Magee’s findings add further weight to a growing body of evidence which points to Hedgehog signaling as an important driver of pancreatic cancer. To prevent this signaling pathway at its starting point is both a simple and ingenious approach that could herald the development of a new treatment. As developing new treatments and early detection methods are the core focus of the Pancreatic Cancer Research Fund, we await further announcements with great anticipation.”
Each year approximately 8,800 people in the U.K. are diagnosed with pancreatic cancer. It is an extremely difficult cancer to diagnose and treat because it is unusually aggressive, symptoms are often vague and generally appear at an advanced stage of the disease. Around three percent of those diagnosed with pancreatic cancer will survive for five years or more, a figure that has not improved significantly in forty years.
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