Blocking Activity of Dopamine Receptor Impedes Growth and Spread of Pancreatic Cancer

Cancer researchers have found that a receptor protein that binds natural compounds such as dopamine and extraneous factors such as antipsychotic drugs to brain cells could inhibit the growth of pancreatic cancer and prevent it from metastasizing.

Since almost all those diagnosed with pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, die from the disease, better treatments are urgently needed. To this end, investigators at the German Cancer Research Center (Heidelberg) and collaborators in the United Kingdom, Italy, and Canada analyzed gene expression profiles of PDACs and the functions of genes with altered expression to identify new therapeutic targets.

The investigators performed microarray analyses to determine gene expression profiles of 195 PDAC and 41 non-tumor pancreatic tissue samples. They also performed tissue microarray analyses to verify changes in expression of candidate proteins using an independent set of 152 samples (40 non-tumor pancreatic tissues, 63 PDAC sections, and 49 chronic pancreatitis samples).

They reported in the August 28, 2016, online edition of the journal Gastroenterology that analysis of 38,276 human genes and loci yielded 1676 genes that were significantly upregulated and 1166 genes that were significantly downregulated in PDAC, compared with non-tumor pancreatic tissues. One gene that was upregulated and associated with multiple signaling pathways that were dysregulated in PDAC was G protein subunit alpha i2 (GNAI2), which had not been previously associated with PDAC. GNAI2 mediates the effects of dopamine receptor D2 (DRD2) on cAMP signaling, and PDAC tissues had a slight but significant increase in DRD2 mRNA. Levels of DRD2 protein were substantially increased in PDACs, compared with non-tumor tissues, in tissue microarray analyses.

Knockdown of DRD2 by microRNA inhibition (RNAi) or by inhibition with pharmacologic drugs (pimozide and haloperidol) reduced proliferation of pancreatic cancer cells, induced endoplasmic reticulum stress and apoptosis, and reduced cell migration. RNAi knockdown of DRD2 in pancreatic tumor cells reduced growth of xenograft tumors in mice, and administration of the DRD2 inhibitor haloperidol to mice with xenograft tumors reduced final tumor size and metastasis.

"The [pancreatic] tumors do not cause any signs or symptoms for a long time and are therefore diagnosed late," said senior author Dr. Jörg Hoheisel head of the division of functional genome analysis at the German Cancer Research Center. "In addition, the tumor biology is very aggressive, i.e., the cancer starts spreading metastases early on. And to make things worse, pancreatic cancer rapidly develops resistance against available chemotherapy drugs."

"We do not know yet whether haloperidol or related medications have the same effect in pancreatic cancer patients as they have in tumor cells and mice," said Dr. Hoheisel. "It is therefore possible that the cancer-inhibiting effect might not be restricted to the pancreas. We are very lucky to have come across established medications. This should make the required and laborious safety examinations easier."

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German Cancer Research Center