Inhibition of MELK produces potential anti‐tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway

Abstract

We aimed to investigate the biological function of MELK and the therapeutic potential of OTSSP167 in human bladder cancer (BCa). First, we observed overexpression of MELK in BCa cell lines and tissues and found that it was associated with higher tumour stage and tumour grade, which was consistent with transcriptome analysis.High expression of MELK was significantly correlated with poor prognosis in BCa patients, and MELK was found to have a role in the cell cycle, the G1/S transition in mitosis, and DNA repair and replication. Furthermore, BCa cells presented significantly decreased proliferation capacity following silencing of MELK or treatment with OTSSP167 in vitro and in vivo. Functionally, reduction in MELK or treatment of cells with OTSSP167 could induce cell cycle arrest and could suppress migration. In addition, these treatments could activate phosphorylation of ATM and CHK2, which would be accompanied by down-regulated MDMX, cyclin D1, CDK2 and E2F1; however, p53 and p21 would be activated. Opposite results were observed when MELK expression was induced. Overall, MELK was found to be a novel oncogene in BCa that induces cell cycle arrest via the ATM/CHK2/p53 pathway. OTSSP167 displays potent anti-tumour activities, which may provide a new molecule-based strategy for BCa treatment. K E Y W O R D S bladder cancer, cell cycle, MELK, OTSSP167, p53 | 1805 CHEN Et al.

Enigmatic MELK: The controversy surrounding its complex role in cancer

“…Numerous studies have used microarray and TCGA analysis or immunoblotting methods to demonstrate that expression of MELK RNA or protein is significantly increased in neoplastic cells. This effect seems to be a characteristic that broadly defines many cancer types, as it has been described in breast (17, 21, 22), brain (glioma (6, 23), astrocytoma (24), and neuro-blastoma (25)), liver (26), prostate (8), bladder (27), and endometrial cancers (28), among others (5). Further, high levels of MELK expression correlate with high-grade tumors, increased aggressiveness, poor patient outcomes, and radioresistance (17,21,22,(25)(26)(27)(28)(29).…”

“…This effect seems to be a characteristic that broadly defines many cancer types, as it has been described in breast (17, 21, 22), brain (glioma (6, 23), astrocytoma (24), and neuro-blastoma (25)), liver (26), prostate (8), bladder (27), and endometrial cancers (28), among others (5). Further, high levels of MELK expression correlate with high-grade tumors, increased aggressiveness, poor patient outcomes, and radioresistance (17,21,22,(25)(26)(27)(28)(29). Increased MELK expression has been linked to concurrent up-regulation of genes important or essential for cell cycle progression, including CDK1, CCNB1/2, TOP2A, AURKB, PLK1, and BUB1 (8,24,(30)(31)(32)(33), suggesting that MELK likely also plays a role in this process.…”

“…In the case of MELK, increased expression may affect DNA damage response to influence genetic instability of cancer cells, or it may be important for maintenance of stemness in the cancer stem cell niche. MELK has been linked to both processes previously (27,34,40,46,47). Finally, multiple MELK inhibitors have demonstrated antiproliferative effects, but it is not possible to definitively conclude that the observed effects are due solely to MELK inhibition.…”

DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

“…It has now been confirmed that when DNA damage occurs in G1 cells, the G1/S checkpoint can be triggered via at least two signaling pathways, the ATM/p53/p21 and the ATM/CHK2/CDC25C pathways 216 . For instance, post irradiation, ATM is activated, and ATM phosphorylates p53 and MDM2, promoting dissociation of p53 from MDM2 and inhibiting p53 translocation from the nucleus to cytoplasm; on the other hand, CHK2 is activated, which phosphorylates and stabilizes p53, and the increased level of p53 triggers the transcription of downstream genes such as p21, contributing to G1/S arrest [217][218][219] . Compared to the ATM/p53/p21 pathway, the ATM/CHK2/CDC25C pathway induces rapid signaling in response to DNA damage 220 .…”

BCLAF1 induces cisplatin resistance in lung cancer cells

“…Elevated p21 protein levels have previously been documented to inhibit cyclin D-Cyclin-dependent kinase (CDK) 4/6 activity, contributing to G 1 phase cell cycle arrest (28)(29)(30). The p21 mRNA level was decreased in A549/DDP cells depletion of BCLAF1 (Fig.…”