中文
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Cancer cells are defective in DNA repair, so they experience increased DNA strand breaks (DSBs), genome instability, gene mutagenesis, and tumorigenicity; however, multiple classic DNA repair genes and pathways are strongly activated in malignant tumor cells to compensate for the DNA repair deficiency and gain an apoptosis resistance. The mechanisms underlying this phenomenon in cancer are unclear. We speculate that a key DNA repair gene or signaling pathway in cancer has not yet been recognized. Here, we show that the lipogenic liver X receptor (LXR)-sterol response element binding factor-1 (SREBF1) axis controls the transcription of a key DNA repair gene polynucleotide kinase/phosphatase (PNKP), thereby governing cancer cell DNA repair and apoptosis. Notably the PNKP levels were significantly reduced in 95% of human pancreatic cancer patients, particularly deep reduction for 6-fold in all of the advanced-stage pancreatic cancer cases. PNKP is also deficient in three other types of cancer that we examined. Additionally, the expression of LXR and SREBF1 was significantly reduced in the tumor tissues from human pancreatic cancer patients compared to the adjacent normal tissues. The newly identified LXR-SREBF1-PNKP signaling pathway is deficient in pancreatic cancer, and the defect in the pathway contributes to the DNA repair deficiency in the cancer. Strikingly, further diminution of the vulnerable LXR-SREBF1-PNKP signaling pathway using a small molecule triptonide, a new LXR antagonist identified in this investigation, at a concentration of 8 nM robustly activated tumor suppressor p53 and readily elevated cancer cell DSBs over an apoptotic threshold, and selectively induced pancreatic cancer cell apoptosis, resulting in almost complete elimination of tumors in xenograft mice without obvious complications.Our findings provide new insight into DNA repair and apoptosis in cancer, and offer a new platform for developing novel anticancer therapeutics.
The LXRs-SREBF1-PNKP axis is essential for DNA repair in cancer cells and is a vulnerable point of pancreatic cancer for effective cancer therapy.
Hydrophobic triptonide (TN) passes through the cell membrane and directly binds to its receptor liver X receptors (LXRα and/or LXRβ), inhibits the transcriptional activity of LXRs and reduces the expression of LXR-downstream transcription factor SREBF1 gene, in turn diminishing SREBF1-downstream PNKP gene expression. The LXRs-SREBF1-PNKP signaling axis controls the levels of intracellular DNA double-strand breaks (DSBs) and DNA repair in pancreatic cancer (PC) cells. Reduction of the LXRs-SREBF1-PNKP axis by triptonide causes a severe defect in DNA repair, marked elevation of intracellular DSBs, activation of p53, and induction of PC cell mitotic catastrophe and apoptosis, resulting in marked reduction of PC cell tumorigenicity and potent anti-PC effects without obvious complications in murine studies.