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Open Access 27-03-2024 | Original Article

A polo-like kinase 1 inhibitor enhances erastin sensitivity in head and neck squamous cell carcinoma cells in vitro

Authors: Xiangping Wu, Jing Wu

Published in: Cancer Chemotherapy and Pharmacology

Abstract

Background

Polo-like kinase 1 (PLK1) is a critical therapeutic target in the treatment of head and neck squamous cell carcinoma (HNSCC). The objective of this study was to investigate the therapeutic effect of the combination of BI 2536, a PLK1 inhibitor, and erastin, a ferroptosis inducer, in HNSCC.

Methods

The proliferation, invasion, and migration abilities of Tu177 and FaDu cells upon exposure to BI 2536 and erastin, used in combination or alone, were tested. Fe²⁺, glutathione (GSH), and malondialdehyde (MDA) detection kits were used to determine whether the addition of BI 2536 enhanced the accumulation of Fe²⁺ and MDA, along with the depletion of GSH. Quantitative real-time PCR, western blot analyses were performed to investigate whether BI 2536 further altered the mRNA and expression level of ferroptosis genes. Furthermore, si PLK1 was used to investigate whether targeting PLK1 gene promoted erastin-induced ferroptosis.

Results

The combination of BI 2536 and erastin exerted a stronger cytotoxicity than treatment with a single agent. Compared with erastin treatment alone, the combination of BI 2536 and erastin lowered the ability of tumor cells to self-clone, invade, and migrate. BI 2536 enhanced the accumulation of Fe²⁺ and MDA, and the depletion of GSH. BI 2536 increased erastin-induced changes in ferroptosis-related gene mRNA and expression. Importantly, targeting PKL1 enhanced the anti-cancer effect of erastin.

Conclusion

BI 2536 enhanced the sensitivity of HNSCC cells to erastin, which provides a new perspective for cancer treatment.

Day AT, Sher DJ, Lee RC, Truelson JM, Myers LL, Sumer BD, Stankova L, Tillman BN, Hughes RS, Khan SA, Gordin EA (2020) Head and neck oncology during the COVID-19 pandemic: reconsidering traditional treatment paradigms in light of new surgical and other multilevel risks. Oral Oncol 105:104684. https://doi.org/10.1016/j.oraloncology.2020.104684CrossRefPubMedPubMedCentral

Lee NY, Ferris RL, Psyrri A, Haddad RI, Tahara M, Bourhis J, Harrington K, Chang PM-H, Lin J-C, Razaq MA, Teixeira MM, Lövey J, Chamois J, Rueda A, Hu C, Dunn LA, Dvorkin MV, De Beukelaer S, Pavlov D, Thurm H, Cohen E (2021) Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol 22:450–462. https://doi.org/10.1016/s1470-2045(20)30737-3CrossRefPubMed

Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR (2020) Head and neck squamous cell carcinoma. Nat Rev Dis Prim 6:92. https://doi.org/10.1038/s41572-020-00224-3CrossRefPubMed

Xia Y, Liu S, Li C, Ai Z, Shen W, Ren W, Yang X (2020) Discovery of a novel ferroptosis inducer-talaroconvolutin A—killing colorectal cancer cells in vitro and in vivo. Cell Death Dis 11:988. https://doi.org/10.1038/s41419-020-03194-2CrossRefPubMedPubMedCentral

Yan HF, Zou T, Tuo QZ, Xu S, Li H, Belaidi AA, Lei P (2021) Ferroptosis: mechanisms and links with diseases. Signal Transduct Target Ther 6:49. https://doi.org/10.1038/s41392-020-00428-9CrossRefPubMedPubMedCentral

Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, Irmler M, Beckers J, Aichler M, Walch A, Prokisch H, Trumbach D, Mao G, Qu F, Bayir H, Fullekrug J, Scheel CH, Wurst W, Schick JA, Kagan VE, Angeli JP, Conrad M (2017) ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol 13:91–98. https://doi.org/10.1038/nchembio.2239CrossRefPubMed

Li Y, Feng D, Wang Z, Zhao Y, Sun R, Tian D, Liu D, Zhang F, Ning S, Yao J, Tian X (2019) Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ 26:2284–2299. https://doi.org/10.1038/s41418-019-0299-4CrossRefPubMedPubMedCentral

Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A, Eggenhofer E, Basavarajappa D, Radmark O, Kobayashi S, Seibt T, Beck H, Neff F, Esposito I, Wanke R, Forster H, Yefremova O, Heinrichmeyer M, Bornkamm GW, Geissler EK, Thomas SB, Stockwell BR, O’Donnell VB, Kagan VE, Schick JA, Conrad M (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 16:1180–1191. https://doi.org/10.1038/ncb3064CrossRefPubMed

Koppula P, Zhuang L, Gan B (2021) Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy, protein. Cell 12:599–620. https://doi.org/10.1007/s13238-020-00789-5CrossRef

10.

Wang L, Liu Y, Du T, Yang H, Lei L, Guo M, Ding HF, Zhang J, Wang H, Chen X, Yan C (2020) ATF3 promotes erastin-induced ferroptosis by suppressing system Xc–. Cell Death Differ 27:662–675. https://doi.org/10.1038/s41418-019-0380-zCrossRefPubMed

11.

Lang X, Green MD, Wang W, Yu J, Choi JE, Jiang L, Liao P, Zhou J, Zhang Q, Dow A, Saripalli AL, Kryczek I, Wei S, Szeliga W, Vatan L, Stone EM, Georgiou G, Cieslik M, Wahl DR, Morgan MA, Chinnaiyan AM, Lawrence TS, Zou W (2019) Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov 9:1673–1685. https://doi.org/10.1158/2159-8290.CD-19-0338CrossRefPubMedPubMedCentral

12.

Sun J, Liu Q, Jiang Y, Cai Z, Liu H, Zuo H (2023) Engineered small extracellular vesicles loaded with miR-654–5p promote ferroptosis by targeting HSPB1 to alleviate sorafenib resistance in hepatocellular carcinoma. Cell Death Dis. https://doi.org/10.1038/s41420-023-01660-2CrossRefPubMedPubMedCentral

13.

Friedmann Angeli JP, Krysko DV, Conrad M (2019) Ferroptosis at the crossroads of cancer—acquired drug resistance and immune evasion. Nat Rev Cancer 19:405–414. https://doi.org/10.1038/s41568-019-0149-1CrossRefPubMed

14.

Gheghiani L, Wang L, Zhang Y, Moore XTR, Zhang J, Smith SC, Tian Y, Wang L, Turner K, Jackson-Cook CK, Mukhopadhyay ND, Fu Z (2021) PLK1 induces chromosomal instability and overrides cell-cycle checkpoints to drive tumorigenesis. Can Res 81:1293–1307. https://doi.org/10.1158/0008-5472.Can-20-1377CrossRef

15.

De Martino D, Yilmaz E, Orlacchio A, Ranieri M, Zhao K, Di Cristofano A (2018) PI3K blockage synergizes with PLK1 inhibition preventing endoreduplication and enhancing apoptosis in anaplastic thyroid cancer. Cancer Lett 439:56–65. https://doi.org/10.1016/j.canlet.2018.09.024CrossRefPubMedPubMedCentral

16.

Gao W, Zhang Y, Luo H, Niu M, Zheng X, Hu W, Cui J, Xue X, Bo Y, Dai F, Lu Y, Yang D, Guo Y, Guo H, Li H, Zhang Y, Yang T, Li L, Zhang L, Hou R, Wen S, An C, Ma T, Jin L, Xu W, Wu Y (2020) Targeting SKA3 suppresses the proliferation and chemoresistance of laryngeal squamous cell carcinoma via impairing PLK1–AKT axis-mediated glycolysis. Cell Death Dis. https://doi.org/10.1038/s41419-020-03104-6CrossRefPubMedPubMedCentral

17.

Montaudon E, Nikitorowicz-Buniak J, Sourd L, Morisset L, El Botty R, Huguet L, Dahmani A, Painsec P, Nemati F, Vacher S, Chemlali W, Masliah-Planchon J, Château-Joubert S, Rega C, Leal MF, Simigdala N, Pancholi S, Ribas R, Nicolas A, Meseure D, Vincent-Salomon A, Reyes C, Rapinat A, Gentien D, Larcher T, Bohec M, Baulande S, Bernard V, Decaudin D, Coussy F, Le Romancer M, Dutertre G, Tariq Z, Cottu P, Driouch K, Bièche I, Martin L-A, Marangoni E (2020) PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance. Nat Commun. https://doi.org/10.1038/s41467-020-17697-1CrossRefPubMedPubMedCentral

18.

Yu Z, Deng P, Chen Y, Liu S, Chen J, Yang Z, Chen J, Fan X, Wang P, Cai Z, Wang Y, Hu P, Lin D, Xiao R, Zou Y, Huang Y, Yu Q, Lan P, Tan J, Wu X (2021) Inhibition of the PLK1-coupled cell cycle machinery overcomes resistance to oxaliplatin in colorectal cancer. Adv Sci. https://doi.org/10.1002/advs.202100759CrossRef

19.

Liu Z, Sun Q, Wang X (2017) PLK1, a potential target for cancer therapy. Transl Oncol 10:22–32. https://doi.org/10.1016/j.tranon.2016.10.003CrossRefPubMed

20.

Zhang L, Wang Z, Liu R, Li Z, Lin J, Wojciechowicz ML, Huang J, Lee K, A. Ma’ayan, J.C. He. (2021) Connectivity mapping identifies BI-2536 as a potential drug to treat diabetic kidney disease. Diabetes. https://doi.org/10.2337/db20-0580CrossRefPubMedPubMedCentral

21.

Lin RC, Chao YY, Lien WC, Chang HC, Tsai SW, Wang CY (2023) Polo-like kinase 1 selective inhibitor BI2536 (dihydropteridinone) disrupts centrosome homeostasis via ATM-ERK cascade in adrenocortical carcinoma. Oncol Rep. https://doi.org/10.3892/or.2023.8604CrossRefPubMedPubMedCentral

22.

Wu M, Wang Y, Yang D, Gong Y, Rao F, Liu R, Danna Y, Li J, Fan J, Chen J, Zhang W, Zhan Q (2019) A PLK1 kinase inhibitor enhances the chemosensitivity of cisplatin by inducing pyroptosis in oesophageal squamous cell carcinoma. EBioMedicine 41:244–255. https://doi.org/10.1016/j.ebiom.2019.02.012CrossRefPubMedPubMedCentral

23.

Lian G, Li L, Shi Y, Jing C, Liu J, Guo X, Zhang Q, Dai T, Ye F, Wang Y, Chen M (2018) 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. https://doi.org/10.3892/ijo.2018.4255CrossRefPubMedPubMedCentral

24.

Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, Brown LM, Girotti AW, Cornish VW, Schreiber SL, Stockwell BR (2014) Regulation of ferroptotic cancer cell death by GPX4. Cell 156:317–331. https://doi.org/10.1016/j.cell.2013.12.010CrossRefPubMedPubMedCentral

25.

Yang WS, Stockwell BR (2016) Ferroptosis: death by lipid peroxidation. Trend Cell Biol 26:165–176. https://doi.org/10.1016/j.tcb.2015.10.014CrossRef

26.

Chen G-Q, Benthani FA, Wu J, Liang D, Bian Z-X, Jiang X (2019) Artemisinin compounds sensitize cancer cells to ferroptosis by regulating iron homeostasis. Cell Death Differ 27:242–254. https://doi.org/10.1038/s41418-019-0352-3CrossRefPubMedPubMedCentral

27.

Ghoochani A, Hsu EC, Aslan M, Rice MA, Nguyen HM, Brooks JD, Corey E, Paulmurugan R, Stoyanova T (2021) Ferroptosis inducers are a novel therapeutic approach for advanced prostate cancer. Cancer Res 81:1583–1594. https://doi.org/10.1158/0008-5472.CAN-20-3477CrossRefPubMedPubMedCentral

28.

Yang J, Mo J, Dai J, Ye C, Cen W, Zheng X, Jiang L, Ye L (2021) Cetuximab promotes RSL3-induced ferroptosis by suppressing the Nrf2/HO-1 signalling pathway in KRAS mutant colorectal cancer. Cell Death Dis. https://doi.org/10.1038/s41419-021-04367-3CrossRefPubMedPubMedCentral

29.

Liang C, Zhang X, Yang M, Dong X (2019) Recent progress in ferroptosis inducers for cancer therapy. Adv Mater 31:e1904197. https://doi.org/10.1002/adma.201904197CrossRefPubMed

30.

Stafford JM, Wyatt MD, McInnes C (2023) Inhibitors of the PLK1 polo-box domain: drug design strategies and therapeutic opportunities in cancer. Expert Opin Drug Discov 18:65–81. https://doi.org/10.1080/17460441.2023.2159942CrossRefPubMed

31.

Martin RD, Hébert TE, Tanny JC (2020) Therapeutic targeting of the general RNA polymerase II transcription machinery. Int J Mol Sci. https://doi.org/10.3390/ijms21093354CrossRefPubMedPubMedCentral

Title: A polo-like kinase 1 inhibitor enhances erastin sensitivity in head and neck squamous cell carcinoma cells in vitro
Authors: Xiangping Wu
Jing Wu
Publication date: 27-03-2024
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-024-04654-8

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