title: Enzyme-Instructed Assembly and Disassembly Processes for Targeting Downregulation in Cancer Cells.
abstract: Cancer cells differ from normal cells in both gain of functions (i.e., upregulation) and loss of functions (i.e., downregulation). While it is common to suppress gain of function for chemotherapy, it remains challenging to target downregulation in cancer cells. Here we show the combination of enzyme-instructed assembly and disassembly to target downregulation in cancer cells by designing peptidic precursors as the substrates of both carboxylesterases (CESs) and alkaline phosphatases (ALPs). The precursors turn into self-assembling molecules to form nanofibrils upon dephosphorylation by ALP, but CES-catalyzed cleavage of the ester bond on the molecules results in disassembly of the nanofibrils. The precursors selectively inhibit the cancer cells that downregulate CES (e.g., OVSAHO) but are innocuous to a hepatocyte that overexpresses CES (HepG2), while the two cell lines exhibit comparable ALP activities. This work illustrates a potential approach for the development of chemotherapy via targeting downregulation (or loss of functions) in cancer cells.
authors.affiliation: Department of Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02454, United States.
authors.forename: Zhaoqianqi
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Department of Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02454, United States.
authors.forename: Huaimin
authors.identifier: 0000-0002-8796-0367
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02454, United States.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Department of Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02454, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Chemistry, Brandeis University , 415 South Street, Waltham, Massachusetts 02454, United States.
authors.forename: Bing
authors.identifier: 0000-0002-4639-387X
authors.initials: B
authors.lastname: Xu
mesh_terms: D000469:Alkaline Phosphatase / Q000737:chemistry / Q000378:metabolism*; D002265:Carboxylic Ester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D002265:Carboxylic Ester Hydrolases; D000469:Alkaline Phosphatase