Cisplatin Resistance and Transcription Factors

Abstract

Cisplatin is one of the most potent and widely used anti-cancer agents in the treatment of various solid tumors. However, the development of resistance to cisplatin is a major obstacle in clinical treatment. Several mechanisms are thought to be involved in cisplatin resistance, including decreased intracellular drug accumulation, increased levels of cellular thiols, increased nucleotide excision-repair activity and decreased mismatch-repair activity. In general, the molecules responsible for each mechanism are upregulated in cisplatin-resistant cells; this indicates that the transcription factors activated in response to cisplatin might play crucial roles in drug resistance. It is known that the tumor-suppressor proteins p53 and p73, and the oncoprotein c-Myc, which function as transcription factors, influence cellular sensitivity to cisplatin. So far, we have identified several transcription factors involved in cisplatin resistance, including Y-box binding protein-1 (YB-1), CCAAT-binding transcription factor 2 (CTF2), activating transcription factor 4 (ATF4), zinc-finger factor 143 (ZNF143) and mitochondrial transcription factor A (mtTFA). Two of these-YB-1 and ZNF143-lack the high-mobility group (HMG) domain and can bind preferentially to cisplatin-modified DNA in addition to HMG domain proteins or DNA repair proteins, indicating that these transcription factors may also participate in DNA repair. In this review, we summarize the mechanisms of cisplatin resistance and focus on transcription factors involved in the genomic response to cisplatin.

Twist and p53 reciprocally regulate target genes via direct interaction

“…This strategy makes it easy to identify direct interaction among known proteins. We study the proteins that function in the nuclei of drug-resistant cells (Kohno et al, 2005;Torigoe et al, 2005) and constructed a wide variety of GST-fusion proteins, including DNA repair proteins, chromatin components, transcription factors, transcription related co-factors, protein kinases and antioxidant proteins. Our strategy exhibits a low number of false-positive results, because these proteins are present in the same cells or subcellular compartment at the same time.…”

Enhanced Expression of PCAF Endows Apoptosis Resistance in Cisplatin-Resistant Cells

“…However, the molecular mechanisms of apoptosis resistance have not been studied in cisplatin-resistant cells. We have extensively studied mechanisms involved in cisplatin resistance (1,2). Several mechanisms are involved in the acquisition of cisplatin resistance (3), which include reduced drug accumulation (4,5), increased production of cellular thiol (6,7) and augmented DNA repair activity (8,9).…”

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines

“…Several mechanisms are involved in the acquisition of cisplatin resistance, including decreased drug accumulations (Komatsu et al, 2000;Nakayama et al, 2002), increased levels of cellular glutathione (Lai et al, 1989;Tew, 1994), and increased DNA-repair activity (Chaney and Sancar, 1996;Husain et al, 1998). We have been interested in the transcription factors activated in response to cisplatin, which might play a crucial role in cisplatin resistance (Kohno et al, 2005;Torigoe et al, 2005). We believe that the transcription factors of genes involved in cisplatin resistance are often overexpressed or activated in cisplatin-resistant cells.…”