Journal article
Centriole Overduplication is the Predominant Mechanism Leading to Centrosome Amplification in Melanoma
Molecular cancer research, Vol.16(3), pp.517-527
03/01/2018
DOI: 10.1158/1541-7786.MCR-17-0197
PMCID: PMC5835182
PMID: 29330283
Abstract
Centrosome amplification (CA) is common in cancer and can arise by centriole overduplication or by cell doubling events, including the failure of cell division and cell-cell fusion. To assess the relative contributions of these two mechanisms, the number of centrosomes with mature/mother centrioles was examined by immunofluorescence in a tissue microarray of human melanomas and benign nevi (n = 79 and 17, respectively). The centrosomal protein 170 (CEP170) was used to identify centrosomes with mature centrioles; this is expected to be present in most centrosomes with cell doubling, but on fewer centrosomes with overduplication. Using this method, it was determined that the majority of CA in melanoma can be attributed to centriole overduplication rather than cell doubling events. As Polo-like kinase 4 (PLK4) is the master regulator of centriole duplication, the hypothesis that PLK4 overexpression contributes to centriole overduplication was evaluated. PLK4 is significantly overexpressed in melanoma compared with benign nevi and in a panel of human melanoma cell lines (A375, Hs294T, G361, WM35, WM115,451Lu, and SK-MEL28) compared with normal human melanocytes. Interestingly, although PLK4 expression did not correlate with CA in most cases, treatment of melanoma cells with a selective small-molecule PLK4 inhibitor (centrinone B) significantly decreased cell proliferation. The antiproliferative effects of centrinone B were also accompanied by induction of apoptosis.
Details
- Title: Subtitle
- Centriole Overduplication is the Predominant Mechanism Leading to Centrosome Amplification in Melanoma
- Creators
- Ryan A. Denu - Univ Wisconsin, Sch Med & Publ Hlth, Med Scientist Training Program, Madison, WI USAMaria Shabbir - Univ Wisconsin, Sch Med & Publ Hlth, Dept Dermatol, Madison, WI USAMinakshi Nihal - Univ Wisconsin, Sch Med & Publ Hlth, Dept Dermatol, Madison, WI USAChandra K. Singh - Univ Wisconsin, Sch Med & Publ Hlth, Dept Dermatol, Madison, WI USAB. Jack Longley - Univ Wisconsin, Sch Med & Publ Hlth, Dept Dermatol, Madison, WI USAMark E. Burkard - Univ Wisconsin, Sch Med & Publ Hlth, Div Hematol Oncol, Dept Med, Madison, WI USANihal Ahmad - Univ Wisconsin, Sch Med & Publ Hlth, Dept Dermatol, Madison, WI USA
- Resource Type
- Journal article
- Publication Details
- Molecular cancer research, Vol.16(3), pp.517-527
- Publisher
- Amer Assoc Cancer Research
- DOI
- 10.1158/1541-7786.MCR-17-0197
- PMID
- 29330283
- PMCID
- PMC5835182
- ISSN
- 1541-7786
- eISSN
- 1557-3125
- Number of pages
- 11
- Grant note
- P30AR066524 / National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) P30 CA014520 / University of Wisconsin Carbone Cancer Center Cancer Center 1I01BX00100 / Department of Veterans Affairs (VA Merit Review Award); US Department of Veterans Affairs R01AR059130; R01CA176748; F30CA203271; T32GM008692; UL1TR000427; TL1TR000429 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 03/01/2018
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984700651202771
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