2. Academic Validation
  3. The lipogenic LXR-SREBF1 signaling pathway controls cancer cell DNA repair and apoptosis and is a vulnerable point of malignant tumors for cancer therapy

The lipogenic LXR-SREBF1 signaling pathway controls cancer cell DNA repair and apoptosis and is a vulnerable point of malignant tumors for cancer therapy

  • Cell Death Differ. 2020 Aug;27(8):2433-2450. doi: 10.1038/s41418-020-0514-3.
Bo Yang  # 1 2,  Bin Zhang  # 3 4 5 6 7 8,  Zhifei Cao  # 9 10 11 12 13,  Xingdong Xu 14 15,  Zihe Huo 3 4 5 6,  Pan Zhang 3 4 5 6,  Shufen Xiang 3 4 5 6,  Zhe Zhao 3 4 5 6,  Chunping Lv 3 4 5 6,  Mei Meng 3 4 5 6,  Gaochuan Zhang 16,  Liang Dong 17,  Shucheng Shi 1 2,  Lan Yang 1 2,  Quansheng Zhou 18 19 20 21
Affiliations

Affiliations

  • 1 Department of General Surgery, The Third Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215123, P. R. China.
  • 2 The First People's Hospital of Changzhou, Changzhou, 213003, P. R. China.
  • 3 Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, Suzhou, Jiangsu, 215123, P. R. China.
  • 4 State Key Laboratory of Radiation Medicine, Soochow University, Suzhou, Jiangsu, 215123, P. R. China.
  • 5 Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu, 215123, P. R. China.
  • 6 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, 215123, P. R. China.
  • 7 Center of Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China.
  • 8 Suzhou Institute of Systems Medicine, Suzhou, 215123, China.
  • 9 Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, Suzhou, Jiangsu, 215123, P. R. China. [email protected].
  • 10 State Key Laboratory of Radiation Medicine, Soochow University, Suzhou, Jiangsu, 215123, P. R. China. [email protected].
  • 11 Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu, 215123, P. R. China. [email protected].
  • 12 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, 215123, P. R. China. [email protected].
  • 13 Department of Pathology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215123, P. R. China. [email protected].
  • 14 Department of General Surgery, The People's Hospital of China, Three Gorges University, Yichang, 443000, P. R. China.
  • 15 The First People's Hospital of Yichang, Yichang, 443000, P. R. China.
  • 16 Department of Bioinformatics, College of Basic Medical Science, Soochow University, Suzhou, Jiangsu, 215123, P. R. China.
  • 17 Department of Pathology, College of Basic Medical Science, Soochow University, Suzhou, Jiangsu, 215123, P. R. China.
  • 18 Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, Suzhou, Jiangsu, 215123, P. R. China. [email protected].
  • 19 State Key Laboratory of Radiation Medicine, Soochow University, Suzhou, Jiangsu, 215123, P. R. China. [email protected].
  • 20 Key Laboratory of Thrombosis and Hemostasis, Ministry of Health, Soochow University, Suzhou, Jiangsu, 215123, P. R. China. [email protected].
  • 21 2011 Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, 215123, P. R. China. [email protected].
  • # Contributed equally.
PMID: 32144382 DOI: 10.1038/s41418-020-0514-3
Abstract

Cancer cells are defective in DNA repair, so they experience increased DNA strand breaks, 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 (PC) patients, particularly deep reduction for sixfold in all of the advanced-stage PC cases. PNKP is also deficient in three other types of Cancer that we examined. In addition, the expression of LXRs and SREBF1 was significantly reduced in the tumor tissues from human PC patients compared with the adjacent normal tissues. The newly identified LXR-SREBF1-PNKP signaling pathway is deficient in PC, 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 DNA strand breaks over an apoptotic threshold, and selectively induced PC 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.

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