Bortezomib Targets Sp Transcription Factors in Cancer Cells

• Published in: Molecular pharmacology Vol. 94; no. 4; pp. 1187 - 1196
• Main Authors: Karki, Keshav, Harishchandra, Sneha, Safe, Stephen
• Format: Journal Article
• Language: English
• Published: United States The American Society for Pharmacology and Experimental Therapeutics 01.10.2018
• Subjects: Apoptosis - drug effects; Bortezomib - pharmacology; Caspase 8 - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Down-Regulation - drug effects; Fas-Associated Death Domain Protein - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Humans; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Neoplasms - drug therapy; Neoplasms - metabolism; Sp Transcription Factors - metabolism
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.118.112797

Bortezomib alone and in combination with other anticancer agents are extensively used for chemotherapeutic treatment of multiple myeloma (MM) patients and are being developed for treating other cancers. Bortezomib acts through multiple pathways, and in this study with ANBL-6 and RPMI 8226 MM cells we show that bortezomib inhibited growth and induced apoptosis and that this was accompanied by downregulation of specificity protein (Sp) 1, Sp3, and Sp4 transcription factors that are overexpressed in these cells. Similar results were observed in pancreatic and colon cancer cells. The functional importance of this pathway was confirmed by showing that individual knockdown of Sp1, Sp3, and Sp4 in MM cells inhibited cell growth and induced apoptosis, and that this correlates with the results of previous studies in pancreatic, colon, and other cancer cell lines. The mechanism of bortezomib-mediated downregulation of Sp transcription factors in MM was due to the induction of caspase-8 and upstream factors, including Fas-associated death domain. These results demonstrate that an important underlying mechanism of action of bortezomib was due to the activation of caspase-8-dependent downregulation of Sp1, Sp3, Sp4, and pro-oncogenic Sp-regulated genes.