Novel Survivin Inhibitor for Suppressing Pancreatic Cancer Cells Growth via Downregulating Sp1 and Sp3 Transcription Factors

Abstract

Background/Aims: Targeting survivin, an anti-apoptotic protein and mitotic regulator, is considered as an effective therapeutic option for pancreatic cancer (PaCa). Tolfenamic acid (TA) showed anti-cancer activity in pre-clinical studies. A recent discovery demonstrated a copper(II) complex of TA (Cu-TA) can result in higher activity. In this study, the ability of Cu-TA to inhibit survivin and its transcription factors, Specificity protein (Sp) 1 and 3 in PaCa cell lines and tumor growth in mouse xenograft model were evaluated. Methods: Cell growth inhibition was measured in MIA PaCa-2 and Panc1 cells for 2 days using CellTiter-Glo kit. Sp1, Sp3 and survivin expression (by Western blot and qPCR), apoptotic cells and cell cycle phase distribution (by flow cytometry) were evaluated. A pilot study was performed using athymic nude mice [treated with vehicle/Cu-TA (25 or 50 mg/kg) 3 times/week for 4 weeks. Results: The IC₅₀ value for Cu-TA was about half than TA.Both agents repressed the protein expression of Sp1/Sp3/survivin, Cu-TA was more effective than TA. Especially effect on survivin inhibition was 5.2 (MIA PaCa-2) or 6.4 (Panc1) fold higher and mRNA expression of only survivin was decreased. Apoptotic cells increased with Cu-TA treatment in both cell lines, while Panc1 showed both effect on apoptosis and cell cycle (G₂/M) arrest. Cu-TA decreased the tumor growth in mouse xenografts (25 mg/kg: 48%; 50 mg/kg: 68%). Additionally, there was no change observed in mice body weights, indicating no overt toxicity was occurring. Conclusion: These results show that Cu-TA can serve as an effective survivin inhibitor for inhibiting PaCa cell growth.

Knockdown of LINC00511 promotes radiosensitivity of thyroid carcinoma cells via suppressing JAK2/STAT3 signaling pathway

“…Transcription factors are known to modulate its target genes at transcriptional level. 24,25 Consistently, we uncovered that TAF1 transcriptionally regulated JAK2. LncRNAs have been explained to interact with transcription factors and then further affect its regulation on target genes, 26 thereafter we investigated the relationship among LINC00511, TAF1 and JAK2.…”

“…The regulation of genes was attributed to several factors, among which transcription factors are universally known and researched. 24,25 From UCSC gene browser, we found TAF1, the transcription factor of JAK2 ( Figure 3A). qRT-PCR assay exhibited that TAF1 expression was overtly downregulated in sh-TAF1-transfected TPC-1 and BCPAP cells ( Figure 3B).…”

Emerging Importance of Survivin in Stem Cells and Cancer: the Development of New Cancer Therapeutics

“…TA in combination with Cisplatin has also been shown to reduce survivin levels in pancreatic and ovarian cancers [122,123]. Copper II loaded complex of TA was found to be even more efficient in reducing survivin levels in pancreatic cancers [123]. Plant based Terameprocol which is in phase II studies, inhibits survivin expression in combination with cdc2 in cervical intraepithelial neoplasia.…”

“…Tolfenamic acid (TA) belonging to Nonsteroidal anti-inflammatory drugs ( NSAIDs) causes post translational attenuation of SP1 and Sp3, which in turn results in the downregulation of survivin. TA in combination with Cisplatin has also been shown to reduce survivin levels in pancreatic and ovarian cancers [ 122 , 123 ]. Copper II loaded complex of TA was found to be even more efficient in reducing survivin levels in pancreatic cancers[ 123 ].…”

Targeting the pH Paradigm at the Bedside: A Practical Approach

“…The pain-reliever tolfenamic acid has been safely used for the treatment of cephalea for many years, but now it is only available for veterinary use. Interestingly tolfenamic acid not only downregulates Sp1 but also has many other anti-cancer effects [141][142][143][144][145][146][147][148][149][150][151].…”