Oncogenic roles of TOPK and MELK, and effective growth suppression by small molecular inhibitors in kidney cancer cells

Abstract

T–lymphokine-activated killer cell–originated protein kinase (TOPK) and maternal embryonic leucine zipper kinase (MELK) have been reported to play critical roles in cancer cell proliferation and maintenance of stemness. In this study, we investigated possible roles of TOPK and MELK in kidney cancer cells and found their growth promotive effect as well as some feedback mechanism between these two molecules. Interestingly, the blockade of either of these two kinases effectively caused downregulation of forkhead box protein M1 (FOXM1) activity which is known as an oncogenic transcriptional factor in various types of cancer cells. Small molecular compound inhibitors against TOPK (OTS514) and MELK (OTS167) effectively suppressed the kidney cancer cell growth, and the combination of these two compounds additively worked and showed the very strong growth suppressive effect on kidney cancer cells. Collectively, our results suggest that both TOPK and MELK are promising molecular targets for kidney cancer treatment and that dual blockade of OTS514 and OTS167 may bring additive anti-tumor effects with low risk of side effects.

T-LAK Cell-Originated Protein Kinase (TOPK) as a Prognostic Factor and a Potential Therapeutic Target in Ovarian Cancer

“…Our previous studies showed that inhibition of TOPK kinase activity reduced stability of 2 5 TOPK protein itself through the downregulation of autophosphorylation and resulted in reduction of FOXM1 transcriptional level (11,18). Similarly in ES-2 and SKOV3 ovarian cancer cell lines, we found that TOPK inhibitors reduced TOPK protein level and suppressed transcription of FOXM1, which probably led to the growth inhibition of ovarian cancer cells.…”

“…Expression levels of TOPK protein and FOXM1 mRNA were examined by western blot and RT-PCR, respectively, as described previously (17,18). …”

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

“…4,5 Maternal embryonic leucine zipper kinase (MELK) is a member of the AMP protein kinase (AMPK) family of serine/threonine kinases, and MELK activates multiple cellular pathways that drive oncogenic growth. [8][9][10][11][12][13] It has been shown that MELK is overexpressed in multiple human tumours, including the following: melanoma, 8 diffuse intrinsic pontine glioma (DIPG), 14 breast cancer, 6,15 gastric cancer, 16 high-grade prostate cancer, 17 hepatocellular carcinoma, 18 kidney cancer, 19 small lung cancer, 20 myeloma, 21 acute myeloid leukaemia (AML) 22 and chronic lymphocytic leukaemia (CLL). [8][9][10][11][12][13] It has been shown that MELK is overexpressed in multiple human tumours, including the following: melanoma, 8 diffuse intrinsic pontine glioma (DIPG), 14 breast cancer, 6,15 gastric cancer, 16 high-grade prostate cancer, 17 hepatocellular carcinoma, 18 kidney cancer, 19 small lung cancer, 20 myeloma, 21 acute myeloid leukaemia (AML) 22 and chronic lymphocytic leukaemia (CLL).…”

“…23 High levels of MELK are correlated with clinically aggressive disease and poor survival. 19,[22][23][24][25] A number of studies have shown that MELK inhibition also increases sensitivity to radiation and chemotherapy in pre-clinical adult cancer models, suggesting that combination treatments may also be effective strategies. 19,[22][23][24][25] A number of studies have shown that MELK inhibition also increases sensitivity to radiation and chemotherapy in pre-clinical adult cancer models, suggesting that combination treatments may also be effective strategies.…”

MELK Promotes Melanoma Growth by Stimulating the NF-κB Pathway

“…MELK is highly overexpressed in several cancer types and its inhibition has been shown to block the tumor growth of some cancers (Inoue et al, 2016; Joshi et al, 2013; Kato et al, 2016; Wang et al, 2016; Wang et al, 2014). Interestingly, MELK knockout mice are viable and do not show any specific phenotypes (Wang et al, 2014).…”