MELK, also known as Maternal embryonic leucine zipper kinase, is a member of the AMP-related serine-threonine kinase family. It is involved in regulating many cellular events such as cell proliferation, apoptosis, and metabolism [3,5,6]. MELK has been associated with the PI3K/mTOR pathway, which is crucial for cell growth and survival [1].

The role of MELK in cancer has been a subject of extensive research. In hepatocellular carcinoma (HCC), MELK promotes carcinogenesis. It enhances the activity of PI3K/mTOR signaling, upregulates the cuproptosis-related gene DLAT, stabilizes mitochondrial function, and promotes HCC progression. This effect can be abolished by elesclomol, an agent related to cuproptosis [1]. In TNBC, initial studies using RNAi-mediated MELK depletion showed impaired cancer cell proliferation, but later Nuclease technology-mediated MELK deletion reported unaffected proliferation, leading to controversy regarding its essentiality in cancer [2]. In HCC, murine xenograft assays and lung metastasis mouse models confirmed that MELK facilitates tumorigenesis and metastasis, and its inhibition can stimulate M1 macrophage polarization, hinder M2 macrophage polarization, and recruit CD8 + T-cells [4]. In endometrial carcinoma, MELK promotes cancer progression by activating the mTOR signaling pathway, and its inhibitor OTSSP167 can suppress cell proliferation [7].

In conclusion, MELK plays a significant role in cancer development and progression, influencing multiple cellular processes and signaling pathways. Studies using genetic models like murine xenograft assays, which can be considered as in vivo models relevant to gene knockout or conditional knockout concepts, have been crucial in revealing MELK's functions in specific cancer conditions, highlighting its potential as a therapeutic target in various cancers.

References:

1. Li, Zhipeng, Zhou, Huaxin, Zhai, Xiangyu, Wang, Wei, Jin, Bin. 2023. MELK promotes HCC carcinogenesis through modulating cuproptosis-related gene DLAT-mediated mitochondrial function. In Cell death & disease, 14, 733. doi:10.1038/s41419-023-06264-3. https://pubmed.ncbi.nlm.nih.gov/37949877/

2. McDonald, Ian M, Graves, Lee M. 2020. Enigmatic MELK: The controversy surrounding its complex role in cancer. In The Journal of biological chemistry, 295, 8195-8203. doi:10.1074/jbc.REV120.013433. https://pubmed.ncbi.nlm.nih.gov/32350113/

3. Thangaraj, Karthik, Ponnusamy, Lavanya, Natarajan, Sathan Raj, Manoharan, Ravi. 2020. MELK/MPK38 in cancer: from mechanistic aspects to therapeutic strategies. In Drug discovery today, 25, 2161-2173. doi:10.1016/j.drudis.2020.09.029. https://pubmed.ncbi.nlm.nih.gov/33010478/

4. Tang, Bufu, Zhu, Jinyu, Shi, Yueli, Chen, Minjiang, Ji, Jiansong. 2024. Tumor cell-intrinsic MELK enhanced CCL2-dependent immunosuppression to exacerbate hepatocarcinogenesis and confer resistance of HCC to radiotherapy. In Molecular cancer, 23, 137. doi:10.1186/s12943-024-02049-0. https://pubmed.ncbi.nlm.nih.gov/38970074/

5. Ren, Ling, Guo, Jing-Si, Li, Yu-Heng, Dong, Gang, Li, Xin-Yang. 2022. Structural classification of MELK inhibitors and prospects for the treatment of tumor resistance: A review. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 156, 113965. doi:10.1016/j.biopha.2022.113965. https://pubmed.ncbi.nlm.nih.gov/36411642/

6. Su, Pengfei, Lu, Qiliang, Wang, Yuanyu, Mou, Yiping, Jin, Weiwei. 2024. Targeting MELK in tumor cells and tumor microenvironment: from function and mechanism to therapeutic application. In Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico, 27, 887-900. doi:10.1007/s12094-024-03664-5. https://pubmed.ncbi.nlm.nih.gov/39187643/

7. Xu, Qinyang, Ge, Qiulin, Zhou, Yang, Zhang, Zhigang, Teng, Yincheng. 2020. MELK promotes Endometrial carcinoma progression via activating mTOR signaling pathway. In EBioMedicine, 51, 102609. doi:10.1016/j.ebiom.2019.102609. https://pubmed.ncbi.nlm.nih.gov/31915116/