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Inhibition of stearoyl‐CoA desaturase suppresses growth of pancreatic tumors in vitro and in vivo
Author(s) -
Skrypek Kaitlin,
Balog Steven,
Asahina Kinji
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.06017
Subject(s) - unfolded protein response , cancer research , matrigel , organoid , pancreatic cancer , atf6 , chemistry , biology , apoptosis , cancer , microbiology and biotechnology , biochemistry , angiogenesis , genetics
Pancreatic ductal adenocarcinoma (PDAC) is a relatively rare cancer type, but is the fourth‐leading cause of cancer death in the US. Although chemotherapy and immunotherapy have been used for patients with PDAC, the overall five‐year survival rate is 8% and there is an urgent need for effective therapies. Stearoyl‐CoA desaturase (SCD) is an enzyme localized in the endoplasmic reticulum and generates monounsaturated fatty acid from saturated fatty acid by introducing a single double bond. In the present study, we examined the role of lipid metabolism regulated by SCD in PDAC growth and survival using Pdx1 Cre ; LSL‐Kras G12D mice and human PDAC cell lines. We isolated pancreatic tumors expressing epithelial cellular adhesion molecule by magnetic‐activated cell sorting from the Pdx1 Cre ; LSL‐Kras G12D mouse pancreas and formed tumor organoids in matrigel. We found that a specific SCD inhibitor (A939572) induces degeneration of the tumor organoids. Interestingly, addition of oleic acid (18:1), but not stearic acid (18:0), rescued the inhibitor‐induced degeneration of tumor organoids. Treatment with the SCD inhibitor increased mRNA expression of unfolded protein response (UPR) markers, such as Atf4, Atf6, Ddit3 , spliced Xbp1 , and Grp78 in organoids. The increased expression of these genes was reversed by addition of oleic acid, but not stearic acid. Similarly, the SCD inhibitor suppressed the proliferation of PANC‐1, a human PDAC cell line. The SCD inhibitor induced the expression of the UPR markers in PANC‐1 and their induction was suppressed by oleic acid, but not by stearic acid. After injection of the SCD inhibitor to Pdx1 Cre ; LSL‐Kras G12D mice bearing pancreatic tumors, we observed TUNEL+ cells in pancreatic tumors, but not in normal acinar cells. Our data suggest that the inhibition of SCD causes UPR and cell death in pancreatic tumors. Support or Funding Information Pilot project funding from NIH/NIAAA grant P50 AA011999, USC Dean’s pilot project program