title: Merkel cell carcinoma dependence on bcl-2 family members for survival.
abstract: Merkel cell carcinoma (MCC), a rare but aggressive cutaneous neoplasm with high metastatic potential, has a poor prognosis at late stages of disease with no proven chemotherapeutic regimens. Using an enriched culture medium, we established and characterized 11 MCC cell lines for Bcl-2 family profiling and functional studies. Immunoblot analysis revealed collectively high protein levels of prosurvival Bcl-2 members in cell lines and a panel of MCC tumors. Downregulation of individual Bcl-2 proteins by RNAi promoted death in a subset of MCC cell lines, whereas simultaneous inhibition of multiple family members by using the small-molecule antagonist ABT-263 led to a marked induction of cell death in 10 of 11 lines. ABT-263 induced Bax-dependent apoptosis with rapid cleavage of caspase-3 and PARP, regardless of Bcl-2 family profile or the presence of Merkel cell polyomavirus. Furthermore, ABT-263 treatment led to rapid and sustained growth suppression of MCC xenografts from a representative cell line, accompanied by a striking increase in apoptosis. Our results establish that concurrent inhibition of multiple prosurvival Bcl-2 proteins leads to effective induction of apoptosis, and strongly support the concept that targeting MCC dependence on these molecules may be useful therapeutically by reversing an intrinsic resistance to cell death.
authors.affiliation: Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA. Electronic address: moniquev@umich.edu.
authors.forename: Monique E
authors.initials: ME
authors.lastname: Verhaegen
authors.affiliation: Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Doris
authors.initials: D
authors.lastname: Mangelberger
authors.affiliation: Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Jack W
authors.initials: JW
authors.lastname: Weick
authors.affiliation: Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Tracy D
authors.initials: TD
authors.lastname: Vozheiko
authors.affiliation: Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA; Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA; Michigan Center for Translational Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Harms
authors.affiliation: Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Nash
authors.affiliation: Howard Hughes Medical Institute, Life Sciences Institute, Department of Internal Medicine and Center for Stem Cell Biology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Elsa
authors.initials: E
authors.lastname: Quintana
authors.affiliation: Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Baciu
authors.affiliation: Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA; Department of Otolaryngology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA; Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Johnson
authors.affiliation: Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Bichakjian
authors.affiliation: Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA; Department of Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA. Electronic address: dlugosza@umich.edu.
authors.forename: Andrzej A
authors.initials: AA
authors.lastname: Dlugosz
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015266:Carcinoma, Merkel Cell / Q000473:pathology* / Q000821:virology; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D006801:Humans; D008297:Male; D059965:Merkel cell polyomavirus / Q000302:isolation & purification; D051379:Mice; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D012878:Skin Neoplasms / Q000473:pathology* / Q000821:virology; D013449:Sulfonamides / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000502:physiology
chemical_list: D000814:Aniline Compounds; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; C528561:navitoclax