title: Nitrogen permease regulator-like 2 enhances sensitivity to oxaliplatin in colon cancer cells.
abstract: Colorectal cancer (CRC) is the third most common cancer worldwide. Chemotherapeutic compounds used for the treatment of CRC include oxaliplatin (L-OHP). While L-OHP improves CRC survival, certain patients are resistant. The nitrogen permease regulator like-2 (NPRL2) gene is a candidate tumor suppressor gene that resides in a 120-kb homozygous deletion region on chromosome 3p21.3. In the present study, it was demonstrated that NPRL2 overexpression increases the sensitivity of HCT116 cells to L-OHP. The IC50 of L-OHP was decreased in cells transduced with NPRL2 compared with negative control (NC) cells and the effect of NPRL2 on L-OHP sensitivity was time dependent. Following NPRL2 transduction in HCT116 cells, the cell cycle was arrested in the G1 phase and a partial decrease in the S phase population was observed. Flow cytometric analysis revealed that NPRL2 transduction and L-OHP treatment increased apoptosis compared with NC cells. The mechanism through which NPRL2 overexpression enhances L-OHP sensitivity involves downregulation of the functions of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin network. Furthermore, L-OHP upregulated caspase-3 and caspase-9 to promote apoptosis in NPRL2-overexpressing cells compared with cells that were transduced with NPRL2 or treated with L-OHP and NC cells (P<0.01). NPRL2 overexpression led to the downregulation of CD24, which could significantly reduce tumor invasiveness and decrease the metastatic capacity of HCT116 cells. These mechanisms are likely active in other types of cancer and may be exploited for the development of novel cancer therapies.
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150080, P.R. China.
authors.forename: Ming-Na
authors.initials: MN
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150080, P.R. China.
authors.forename: Ai-Yun
authors.initials: AY
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150080, P.R. China.
authors.forename: Ya-Ju
authors.initials: YJ
authors.lastname: Du
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150080, P.R. China.
authors.forename: Feng-Hua
authors.initials: FH
authors.lastname: Pei
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150080, P.R. China.
authors.forename: Xin-Hong
authors.initials: XH
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150080, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150080, P.R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150080, P.R. China.
authors.forename: Bing-Rong
authors.initials: BR
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D045325:HCT116 Cells; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051927:CD24 Antigen; D053148:Caspase 3; D053453:Caspase 9; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C497889:CD24 protein, human; C492816:NPRL2 protein, human; C546842:MTOR protein, human