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

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

Research output: Contribution to journalArticlepeer-review

Abstract

Adrenocortical carcinoma (ACC) is a rare but malig‑ nant 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, centro‑ some 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.

Original languageEnglish
Article number167
JournalOncology Reports
Volume50
Issue number3
DOIs
Publication statusPublished - 2023 Sept

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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