ASR488, a novel small molecule, activates an mRNA binding protein, CPEB1, and inhibits the growth of bladder cancer

Tyagi,Ashish; Kolluru,Venkatesh; Chandrasekaran,Balaji; Saran,Uttara; Sharma,Arun   K.; Ankem,Murali   K.; Damodaran,Chendil

doi:10.3892/ol.2020.11593

ASR488, a novel small molecule, activates an mRNA binding protein, CPEB1, and inhibits the growth of bladder cancer

Authors:
- Ashish Tyagi
- Venkatesh Kolluru
- Balaji Chandrasekaran
- Uttara Saran
- Arun K. Sharma
- Murali K. Ankem
- Chendil Damodaran
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Affiliations: Department of Urology, University of Louisville, Louisville, KY 40202, USA, Department of Pharmacology, Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA 17033, USA
Published online on: May 7, 2020 https://doi.org/10.3892/ol.2020.11593
Pages: 850-860
Copyright: © Tyagi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Due to a lack of mechanistic insights, muscle‑invasive bladder cancer (MIBC) remains incurable and is one of the most lethal types of cancer in the United States. The present study investigated changes in the molecular signatures of MIBC cells (TCCSUP and HT1376) after treatment with a novel small molecule, ASR488, to gain knowledge of the mechanisms that inhibited MIBC cell growth. ASR488 treatment initiated apoptotic signaling in MIBC cells. Pathway enrichment analysis was used to analyze the changes in function of differentially expressed genes. Gene Ontology analysis, as well as Kyoto Encyclopedia of Genes and Genomes analysis, was also performed. These analyses along with reactome pathway enrichment analyses indicated that the genes upregulated in the ASR488‑treated cells are involved in focal adhesion, neurotrophin signaling, p53 signaling, endoplasmic reticulum functioning in terms of protein processing, and pathways related to bladder cancer. The genes downregulated in ASR488‑treated MIBC cells were mainly involved in DNA replication, mismatch repair, RNA degradation, nucleotide excision repair and TGFβ signaling (P<0.05). Furthermore, reverse transcription‑quantitative PCR analysis revealed an increase in transcripts of the most upregulated genes in ASR 488‑treated MIBC cells: CPEB1 (36‑fold), IL11 (30‑fold), SFN (20.12‑fold) and CYP4F11 (15.8‑fold). In conclusion, the analysis of biological functions of the most differentially expressed genes revealed possible mechanisms that may be associated with the aggressiveness of MIBC.

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1	Liang Y, Zhu F, Zhang H, Chen D, Zhang X, Gao Q and Li Y: Conditional ablation of TGF-β signaling inhibits tumor progression and invasion in an induced mouse bladder cancer model. Sci Rep. 6:294792016. View Article : Google Scholar : PubMed/NCBI
2	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2018. CA Cancer J Clin. 68:7–30. 2018. View Article : Google Scholar : PubMed/NCBI
3	Erlich A and Zlotta AR: Treatment of bladder cancer in the elderly. Investig Clin Urol. 57 (Suppl 1):S26–S35. 2016. View Article : Google Scholar : PubMed/NCBI
4	van den Bosch S and Alfred Witjes J: Long-term cancer-specific survival in patients with high-risk, non-muscle-invasive bladder cancer and tumour progression: A systematic review. Eur Urol. 60:493–500. 2011. View Article : Google Scholar : PubMed/NCBI
5	Pectasides D, Pectasides M and Nikolaou M: Adjuvant and neoadjuvant chemotherapy in muscle invasive bladder cancer: Literature review. Eur Urol. 48:60–68. 2005. View Article : Google Scholar : PubMed/NCBI
6	Akand M, Kilic Ö, Harmankaya I, Karabagli P, Yavas Ç and Ata Ö: Aggressive treatment for urothelial cancer-complete urinary tract extirpation: Operative feasibility in two cases. Turk J Urol. 45:393–397. 2018. View Article : Google Scholar : PubMed/NCBI
7	Mathes J, Rausch S, Todenhöfer T and Stenzl A: Trimodal therapy for muscle-invasive bladder cancer. Expert Rev Anticancer Ther. 18:1219–1229. 2018. View Article : Google Scholar : PubMed/NCBI
8	Roberts JT, von der Maase H, Sengeløv L, Conte PF, Dogliotti L, Oliver T, Moore MJ, Zimmermann A and Arning M: Long-term survival results of a randomized trial comparing gemcitabine/cisplatin and methotrexate/vinblastine/doxorubicin/cisplatin in patients with locally advanced and metastatic bladder cancer. Ann Oncol. 17 (Suppl 5):v118–v122. 2006. View Article : Google Scholar : PubMed/NCBI
9	Padma VV: An overview of targeted cancer therapy. Biomedicine (Taipei). 5:192015. View Article : Google Scholar : PubMed/NCBI
10	Carter PJ: Potent antibody therapeutics by design. Nat Rev Immunol. 6:343–357. 2006. View Article : Google Scholar : PubMed/NCBI
11	Hoelder S, Clarke PA and Workman P: Discovery of small molecule cancer drugs: Successes, challenges and opportunities. Mol Oncol. 6:155–176. 2012. View Article : Google Scholar : PubMed/NCBI
12	Imai K and Takaoka A: Comparing antibody and small-molecule therapies for cancer. Nat Rev Cancer. 6:714–727. 2006. View Article : Google Scholar : PubMed/NCBI
13	Mu Y and Sun D: Lapatinib, a dual inhibitor of epidermal growth factor receptor (EGFR) and HER-2, enhances radiosensitivity in mouse bladder tumor Line-2 (MBT-2) cells in vitro and in vivo. Med Sci Monit. 24:5811–5819. 2018. View Article : Google Scholar : PubMed/NCBI
14	Hänze J, Kessel F, Di Fazio P, Hofmann R and Hegele A: Effects of multi and selective targeted tyrosine kinase inhibitors on function and signaling of different bladder cancer cells. Biomed Pharmacother. 106:316–325. 2018. View Article : Google Scholar : PubMed/NCBI
15	Yan J, Risacher SL, Shen L and Saykin AJ: Network approaches to systems biology analysis of complex disease: Integrative methods for multi-omics data. Brief Bioinform. 19:1370–1381. 2018.PubMed/NCBI
16	Tyagi A, Chandrasekaran B, Kolluru V, Rai S, Jordan AC, Houda A, Messer J, Ankem M, Damodaran C and Haddad A: Combination of androgen receptor inhibitor and cisplatin, an effective treatment strategy for urothelial carcinoma of the bladder. Urol Oncol. 37:492–502. 2019. View Article : Google Scholar : PubMed/NCBI
17	Pal D, Tyagi A, Chandrasekaran B, Alattasi H, Ankem MK, Sharma AK and Damodaran C: Suppression of Notch1 and AKT mediated epithelial to mesenchymal transition by Verrucarin J in metastatic colon cancer. Cell Death Dis. 9:7982018. View Article : Google Scholar : PubMed/NCBI
18	Bellmunt J, Powles T and Vogelzang NJ: A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now. Cancer Treat Rev. 54:58–67. 2017. View Article : Google Scholar : PubMed/NCBI
19	Sundararajan S and Vogelzang NJ: Anti-PD-1 and PD-L1 therapy for bladder cancer: What is on the horizon? Future Oncol. 11:2299–2306. 2015. View Article : Google Scholar : PubMed/NCBI
20	Deng J, Peng M, Wang Z, Zhou S, Xiao D, Deng J and Yang X, Peng J and Yang X: Novel application of metformin combined with targeted drugs on anticancer treatment. Cancer Sci. 110:23–30. 2019. View Article : Google Scholar : PubMed/NCBI
21	Nagaoka K, Fujii K, Zhang H, Usuda K, Watanabe G, Ivshina M and Richter JD: CPEB1 mediates epithelial-to-mesenchyme transition and breast cancer metastasis. Oncogene. 35:2893–2901. 2016. View Article : Google Scholar : PubMed/NCBI
22	Grudzien-Nogalska E, Reed BC and Rhoads RE: CPEB1 promotes differentiation and suppresses EMT in mammary epithelial cells. J Cell Sci. 127:2326–2338. 2014. View Article : Google Scholar : PubMed/NCBI
23	Chen Y, Tsai YH and Tseng SH: Regulation of the expression of cytoplasmic polyadenylation element binding proteins for the treatment of cancer. Anticancer Res. 36:5673–5680. 2016. View Article : Google Scholar : PubMed/NCBI
24	Burns DM and Richter JD: CPEB regulation of human cellular senescence, energy metabolism, and p53 mRNA translation. Genes Dev. 22:3449–3460. 2008. View Article : Google Scholar : PubMed/NCBI
25	Putoczki TL, Thiem S, Loving A, Busuttil RA, Wilson NJ, Ziegler PK, Nguyen PM, Preaudet A, Farid R, Edwards KM, et al: Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell. 24:257–271. 2013. View Article : Google Scholar : PubMed/NCBI
26	Ernst M and Putoczki TL: Targeting IL-11 signaling in colon cancer. Oncotarget. 4:1860–1861. 2013. View Article : Google Scholar : PubMed/NCBI
27	Johnstone CN, Chand A, Putoczki TL and Ernst M: Emerging roles for IL-11 signaling in cancer development and progression: Focus on breast cancer. Cytokine Growth Factor Rev. 26:489–498. 2015. View Article : Google Scholar : PubMed/NCBI
28	Wu D, Tao J, Ding J, Qu P, Lu Q and Zhang W: Interleukin-11, an interleukin-6-like cytokine, is a promising predictor for bladder cancer prognosis. Mol Med Rep. 7:684–688. 2013. View Article : Google Scholar : PubMed/NCBI
29	Khajah MA, Mathew PM and Luqmani YA: Na⁺/K⁺ ATPase activity promotes invasion of endocrine resistant breast cancer cells. PLoS One. 13:e01937792018. View Article : Google Scholar : PubMed/NCBI
30	Wang H, Zuo Y, Ding M, Ke C, Yan R, Zhan H, Liu J, Wang W, Li N and Wang J: LASS2 inhibits growth and invasion of bladder cancer by regulating ATPase activity. Oncol Lett. 13:661–668. 2017. View Article : Google Scholar : PubMed/NCBI