PT  - JOURNAL ARTICLE
AU  - Keshav Karki
AU  - Sneha Harishchandra
AU  - Stephen H. Safe
TI  - Bortezomib Targets Sp Transcription Factors in Cancer Cells
AID  - 10.1124/mol.118.112797
DP  - 2018 Jan 01
TA  - Molecular Pharmacology
PG  - mol.118.112797
4099  - http://molpharm.aspetjournals.org/content/early/2018/08/16/mol.118.112797.short
4100  - http://molpharm.aspetjournals.org/content/early/2018/08/16/mol.118.112797.full
AB  - 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 this was accompanied by downregulation of Sp1, 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 this correlates with 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 induction of caspase-8 and upstream factors including Fas-associated death domain (FADD). These results demonstrate that an important underlying mechanism of action of bortezomib was due to activation of caspase-8-dependent downregulation of Sp1, Sp3, Sp4 and pro-oncogenic Sp-regulated genes.