Polo‑like kinase 1 selective inhibitor BI2536 (dihydropteridinone) disrupts centrosome homeostasis via ATM‑ERK cascade in adrenocortical carcinoma

Lin,Ruei-Ci; Chao,Yu-Ying; Lien,Wei-Chih; Chang,Huei-Cih; Tsai,Shih-Wei; Wang,Chia-Yih

doi:10.3892/or.2023.8604

Polo‑like kinase 1 selective inhibitor BI2536 (dihydropteridinone) disrupts centrosome homeostasis via ATM‑ERK cascade in adrenocortical carcinoma

Authors:
- Ruei-Ci Lin
- Yu-Ying Chao
- Wei-Chih Lien
- Huei-Cih Chang
- Shih-Wei Tsai
- Chia-Yih Wang
View Affiliations

Affiliations: Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan, R.O.C., Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 709, Taiwan, R.O.C., Department of Physical Medicine and Rehabilitation, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 709, Taiwan, R.O.C., Department of Obstetrics and Gynecology, An Nan Hospital, China Medical University, Tainan 709, Taiwan, R.O.C.
Published online on: July 20, 2023 https://doi.org/10.3892/or.2023.8604
Article Number: 167
Copyright: © Lin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Adrenocortical carcinoma (ACC) is a rare but malignant tumor. Surgical removal, radiotherapy and combined chemotherapy are commonly used to treat ACC. Despite efforts for several decades, the mortality rate of ACC remains high after treatments. Therefore, identifying a novel therapeutic molecule is important to increase the survival rate of patients with ACC. The centrosome is a microtubule organizing center, and it also functions as a signaling hub to coordinate cell cycle progression. Deficiencies in the regulation of centrosome copy numbers may cause cell cycle arrest or even apoptosis. BI2536 is a polo like kinase 1‑selective inhibitor and has been tested for the treatment of several types of cancer, including lung, oral and gastric cancer. However, to the best of our knowledge, its effects on ACC have not yet been examined. The present study revealed that BI2536 inhibited Y1 ACC cell proliferation in a time‑ and dose‑dependent manner. BI2536 blocked cell cycle progression and also induced cell apoptosis as shown by flow cytometry. Furthermore, following BI2536 treatment, centrosome amplification was induced, which resulted in aberrant mitosis. In terms of the mechanism, BI2536 induced DNA damage as evidenced by γH2AX staining and comet assay, followed by activation of ATM serine/threonine kinase‑ERK signaling to promote centrosome amplification. Therefore, the present study suggested that BI2536 could be used as an adjuvant therapy in the treatment of ACC, and also revealed the underlying molecular mechanism.

View Figures

View References

1	Long SE and Miller BS: Adrenocortical cancer treatment. Surg Clin North Am. 99:759–771. 2019. View Article : Google Scholar : PubMed/NCBI
2	Abiven G, Coste J, Groussin L, Anract P, Tissier F, Legmann P, Dousset B, Bertagna X and Bertherat J: Clinical and biological features in the prognosis of adrenocortical cancer: Poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J Clin Endocrinol Metab. 91:2650–2655. 2006. View Article : Google Scholar : PubMed/NCBI
3	Chen TY, Syu JS, Lin TC, Cheng HL, Lu FL and Wang CY: Chloroquine alleviates etoposide-induced centrosome amplification by inhibiting CDK2 in adrenocortical tumor cells. Oncogenesis. 4:e1802015. View Article : Google Scholar : PubMed/NCBI
4	Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C, Lacroix A, Jarzab B, et al: Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 366:2189–2197. 2012. View Article : Google Scholar : PubMed/NCBI
5	Libé R: Adrenocortical carcinoma (ACC): Diagnosis, prognosis, and treatment. Front Cell Dev Biol. 3:452015. View Article : Google Scholar : PubMed/NCBI
6	Steegmaier M, Hoffmann M, Baum A, Lénárt P, Petronczki M, Krssák M, Gürtler U, Garin-Chesa P, Lieb S, Quant J, et al: BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo. Curr Biol. 17:316–322. 2007. View Article : Google Scholar : PubMed/NCBI
7	Shin SB, Woo SU and Yim H: Differential cellular effects of Plk1 inhibitors targeting the ATP-binding domain or polo-box domain. J Cell Physiol. 230:3057–3067. 2015. View Article : Google Scholar : PubMed/NCBI
8	Matthess Y, Raab M, Knecht R, Becker S and Strebhardt K: Sequential Cdk1 and Plk1 phosphorylation of caspase-8 triggers apoptotic cell death during mitosis. Mol Oncol. 8:596–608. 2014. View Article : Google Scholar : PubMed/NCBI
9	Chen TY, Syu JS, Han TY, Cheng HL, Lu FI and Wang CY: Cell cycle-dependent localization of dynactin subunit p150 glued at centrosome. J Cell Biochem. 116:2049–2060. 2015. View Article : Google Scholar : PubMed/NCBI
10	Lai PY, Wang CY, Chen WY, Kao YH, Tsai HM, Tachibana T, Chang WC and Chung BC: Steroidogenic factor 1 (NR5A1) resides in centrosomes and maintains genomic stability by controlling centrosome homeostasis. Cell Death Differ. 18:1836–1844. 2011. View Article : Google Scholar : PubMed/NCBI
11	Wang CY, Kao YH, Lai PY, Chen WY and Chung BC: Steroidogenic factor 1 (NR5A1) maintains centrosome homeostasis in steroidogenic cells by restricting centrosomal DNA-dependent protein kinase activation. Mol Cell Biol. 33:476–484. 2013. View Article : Google Scholar : PubMed/NCBI
12	Su S, Chhabra G, Singh CK, Ndiaye MA and Ahmad N: PLK1 inhibition-based combination therapies for cancer management. Transl Oncol. 16:1013322022. View Article : Google Scholar : PubMed/NCBI
13	Lian G, Li L, Shi Y, Jing C, Liu J, Guo X, Zhang Q, Dai T, Ye F, Wang Y and Chen M: BI2536, a potent and selective inhibitor of polo-like kinase 1, in combination with cisplatin exerts synergistic effects on gastric cancer cells. Int J Oncol. 52:804–814. 2018.PubMed/NCBI
14	Choi M, Kim W, Cheon MG, Lee CW and Kim JE: Polo-like kinase 1 inhibitor BI2536 causes mitotic catastrophe following activation of the spindle assembly checkpoint in non-small cell lung cancer cells. Cancer Lett. 357:591–601. 2015. View Article : Google Scholar : PubMed/NCBI
15	Wang CY, Huang EY, Huang SC and Chung BC: DNA-PK/Chk2 induces centrosome amplification during prolonged replication stress. Oncogene. 34:1263–1269. 2015. View Article : Google Scholar : PubMed/NCBI
16	Chen TY, Huang BM, Tang TK, Chao YY, Xiao XY, Lee PR, Yang LY and Wang CY: Genotoxic stress-activated DNA-PK-p53 cascade and autophagy cooperatively induce ciliogenesis to maintain the DNA damage response. Cell Death Differ. 28:1865–1879. 2021. View Article : Google Scholar : PubMed/NCBI
17	Wang CY, Tsai HL, Syu JS, Chen TY and Su MT: Primary cilium-regulated EG-VEGF signaling facilitates trophoblast invasion. J Cell Physiol. 232:1467–1477. 2017. View Article : Google Scholar : PubMed/NCBI
18	Teng YN, Chang HC, Chao YY, Cheng HL, Lien WC and Wang CY: Etoposide triggers cellular senescence by inducing multiple centrosomes and primary cilia in adrenocortical tumor cells. Cells. 10:14662021. View Article : Google Scholar : PubMed/NCBI
19	Chao YY, Huang BM, Peng IC, Lee PR, Lai YS, Chiu WT, Lin YS, Lin SC, Chang JH, Chen PS, et al: ATM- and ATR-induced primary ciliogenesis promotes cisplatin resistance in pancreatic ductal adenocarcinoma. J Cell Physiol. 237:4487–4503. 2022. View Article : Google Scholar : PubMed/NCBI
20	Wang CY, Chen WY, Lai PY and Chung BC: Distinct functions of steroidogenic factor-1 (NR5A1) in the nucleus and the centrosome. Mol Cell Endocrinol. 371:148–153. 2013. View Article : Google Scholar : PubMed/NCBI
21	Ferguson RL and Maller JL: Centrosomal localization of cyclin E-Cdk2 is required for initiation of DNA synthesis. Curr Biol. 20:856–860. 2010. View Article : Google Scholar : PubMed/NCBI
22	Ferguson RL, Pascreau G and Maller JL: The cyclin A centrosomal localization sequence recruits MCM5 and Orc1 to regulate centrosome reduplication. J Cell Sci. 123:2743–2749. 2010. View Article : Google Scholar : PubMed/NCBI
23	Bailey LJ, Teague R, Kolesar P, Bainbridge LJ, Lindsay HD and Doherty AJ: PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle. Sci Adv. 7:eabh10042021. View Article : Google Scholar : PubMed/NCBI
24	Nakamura K, Kustatscher G, Alabert C, Hödl M, Forne I, Völker-Albert M, Satpathy S, Beyer TE, Mailand N, Choudhary C, et al: Proteome dynamics at broken replication forks reveal a distinct ATM-directed repair response suppressing DNA double-strand break ubiquitination. Mol Cell. 81:1084–1099.e6. 2021. View Article : Google Scholar : PubMed/NCBI
25	Lee M, Daniels MJ and Venkitaraman AR: Phosphorylation of BRCA2 by the Polo-like kinase Plk1 is regulated by DNA damage and mitotic progression. Oncogene. 23:865–872. 2004. View Article : Google Scholar : PubMed/NCBI
26	Li Z, Li J, Kong Y, Yan S, Ahmad N and Liu X: Plk1 phosphorylation of Mre11 antagonizes the DNA damage response. Cancer Res. 77:3169–3180. 2017. View Article : Google Scholar : PubMed/NCBI
27	Combes G, Alharbi I, Braga LG and Elowe S: Playing polo during mitosis: PLK1 takes the lead. Oncogene. 36:4819–4827. 2017. View Article : Google Scholar : PubMed/NCBI
28	Johnson N, Cai D, Kennedy RD, Pathania S, Arora M, Li YC, D'Andrea AD, Parvin JD and Shapiro GI: Cdk1 participates in BRCA1-dependent S phase checkpoint control in response to DNA damage. Mol Cell. 35:327–339. 2009. View Article : Google Scholar : PubMed/NCBI
29	Ira G, Pellicioli A, Balijja A, Wang X, Fiorani S, Carotenuto W, Liberi G, Bressan D, Wan L, Hollingsworth NM, et al: DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature. 431:1011–1017. 2004. View Article : Google Scholar : PubMed/NCBI