2. Academic Validation
  3. PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma

PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma

  • Sci Transl Med. 2020 Sep 23;12(562):eaay0152. doi: 10.1126/scitranslmed.aay0152.
Tian-Yi Jiang 1 2,  Yu-Fei Pan 2 3,  Zheng-Hua Wan 2,  Yun-Kai Lin 1 2,  Bin Zhu 4,  Zhen-Gang Yuan 4,  Yun-Han Ma 1 2,  Yuan-Yuan Shi 1,  Tian-Mei Zeng 4,  Li-Wei Dong 5 3,  Ye-Xiong Tan 6 3,  Hong-Yang Wang 5 2 3 7 8
Affiliations

Affiliations

  • 1 International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China.
  • 2 National Center for Liver Cancer, Shanghai 201805, China.
  • 3 Shanghai Key Laboratory of Hepato-biliary Tumor Biology, Shanghai 200438, China.
  • 4 Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
  • 5 International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China. dlw@smmu.edu.cn yxtan1214@163.com hywangk@vip.sina.com.
  • 6 National Center for Liver Cancer, Shanghai 201805, China. dlw@smmu.edu.cn yxtan1214@163.com hywangk@vip.sina.com.
  • 7 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China.
  • 8 Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Second Military Medical University & Ministry of Education, Shanghai 200438, China.
PMID: 32967970 DOI: 10.1126/scitranslmed.aay0152
Abstract

Patient-derived xenografts (PDXs) and PDX-derived cells (PDCs) are useful in preclinical research. We performed a drug screening assay using PDCs and identified Proteasome inhibitors as promising drugs for cholangiocarcinoma (CCA) treatment. Furthermore, we determined that phosphate and tensin homology deleted on chromosome ten (PTEN) deficiency promotes protein synthesis and Proteasome subunit expression and proteolytic activity, creating a dependency on the Proteasome for Cancer cell growth and survival. Thus, targeting the Proteasome machinery with the inhibitor bortezomib inhibited the proliferation and survival of CCA cells lacking functional PTEN. Therapeutic evaluation of PDXs, autochthonous mouse models, and patients confirmed this dependency on the Proteasome. Mechanistically, we found that PTEN promoted the nuclear translocation of FOXO1, resulting in the increased expression of BACH1 and MAFF BACH1 and MAFF are transcriptional regulators that recognize the antioxidant response element, which is present in genes encoding Proteasome subunits. PTEN induced the accumulation and nuclear translocation of these proteins, which directly repressed the transcription of genes encoding Proteasome subunits. We revealed that the PTEN-proteasome axis is a potential target for therapy in PTEN-deficient CCA and other PTEN-deficient cancers.

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