Article Data

  • Views 836
  • Dowloads 177

Original Research

Open Access

Suppressing the MLK3 promotes glutamine metabolism: mechanism and implications in progression of colon cancer

  • Ziqi Sui1,2
  • Kejia Wu3
  • Ruiping Shi4
  • Shuqiu Wang1,*,

1Key Laboratory of Microecology-immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, 154000 Jiamusi, Heilongjiang, China

2Department of Gastroenterology, The First People’s Hospital of LinPing District, 310000 Hangzhou, Zhejiang, China

3Department of Endocrinology, First Affiliated Hospital of Jiamusi University, 154000 Jiamusi, Heilongjiang, China

4First Affiliated Hospital of Jiamusi University, 154000 Jiamusi, Heilongjiang, China

DOI: 10.22514/jomh.2023.045 Vol.19,Issue 6,June 2023 pp.26-33

Submitted: 16 April 2023 Accepted: 10 May 2023

Published: 30 June 2023

*Corresponding Author(s): Shuqiu Wang E-mail: wangshuqiu@jmsu.edu.cn

Abstract

This study was designed to explore the potential role of mixed-lineage protein kinase 3 (MLK3) in colorectal cancer (CRC) progression and its relationship with glutamine metabolism. The immunohistochemical staining results of MLK3 were primarily collected through 100 CRC patients. Wound healing and transwell assays were used to detect migration ability of CRC cells by transfecting cells with siMlk3. Gene set variation analysis (GSVA) and Spearman’s rank correlation coefficient were used as bioinformatics tools to explore the signaling pathways related to MLK3. Western blotting was performed to analyze the downstream of glutamine metabolism. The results suggested an increased expression of MLK3 in CRC tissues, which was related to adverse clinicopathological characteristics in those CRC patients. Knockdown of MLK3 inhibited the proliferative and migratory potential of CRCs. Bioinformatics analysis confirmed the relationship between MLK3 expression and cancer malignancy related signaling pathways. CRC cell lines transfected with siMlk3 suppressed glutamine metabolism by downregulating the glutamine transporter alanine-serine-cysteine transporter 2 (ASCT2). These results suggested the vital role of MLK3 in CRC progression, which may be related to the suppression of glutamine transporter, namely alanine, serine, cysteine transporter 2 (ASCT2).


Keywords

Colorectal cancer; MLK3; Glutamine metabolism; ASCT2


Cite and Share

Ziqi Sui,Kejia Wu,Ruiping Shi,Shuqiu Wang. Suppressing the MLK3 promotes glutamine metabolism: mechanism and implications in progression of colon cancer. Journal of Men's Health. 2023. 19(6);26-33.

References

[1] Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA: A Cancer Journal for Clinicians. 2021; 71: 7–33.

[2] Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, et al. Colorectal cancer statistics, 2020. CA: A Cancer Journal for Clinicians. 2020; 70: 145–164.

[3] Wang J, Deng B, Liu Q, Huang Y, Chen W, Li J, et al. Pyroptosis and ferroptosis induced by mixed lineage kinase 3 (MLK3) signaling in cardiomyocytes are essential for myocardial fibrosis in response to pressure overload. Cell Death & Disease. 2020; 11: 574.

[4] Mishra R, Barthwal MK, Sondarva G, Rana B, Wong L, Chatterjee M, et al. Glycogen synthase kinase-3β induces neuronal cell death via direct phosphorylation of mixed lineage kinase 3. The Journal of Biological Chemistry. 2007; 282: 30393–30405.

[5] Rattanasinchai C, Gallo KA. MLK3 signaling in cancer invasion. Cancers. 2016; 8: 51.

[6] Viswakarma N, Sondarva G, Principe DR, Nair RS, Kumar S, Singh SK, et al. Mixed lineage kinase 3 phosphorylates prolyl-isomerase PIN1 and potentiates GLI1 signaling in pancreatic cancer development. Cancer Letters. 2021; 515: 1–13.

[7] Das S, Nair RS, Mishra R, Sondarva G, Viswakarma N, Abdelkarim H, et al. Mixed lineage kinase 3 promotes breast tumorigenesis via phosphorylation and activation of p21-activated kinase 1. Oncogene. 2019; 38: 3569–3584.

[8] Kasturirangan S, Mehdi B, Chadee DN. LATS1 regulates mixed-lineage kinase 3 (MLK3) subcellular localization and MLK3-mediated invasion in ovarian epithelial cells. Molecular and Cellular Biology. 2021; 41: e0007821.

[9] Chen J, Miller EM, Gallo KA. MLK3 is critical for breast cancer cell migration and promotes a malignant phenotype in mammary epithelial cells. Oncogene. 2010; 29: 4399–4411.

[10] Schroyer AL, Stimes NW, Abi Saab WF, Chadee DN. MLK3 phospho-rylation by ERK1/2 is required for oxidative stress-induced invasion of colorectal cancer cells. Oncogene. 2018; 37: 1031–1040.

[11] Kumar S, Singh SK, Viswakarma N, Sondarva G, Nair RS, Sethupathi P, et al. Mixed lineage kinase 3 inhibition induces T cell activation and cytotoxicity. Proceedings of the National Academy of Sciences. 2020; 117: 7961–7970.

[12] Coloff J, Murphy JP, Braun C, Harris I, Shelton L, Kami K, et al. Differential glutamate metabolism in proliferating and quiescent mammary epithelial cells. Cell Metabolism. 2016; 23: 867–880.

[13] Zhang J, Pavlova NN, Thompson CB. Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine. The EMBO Journal. 2017; 36: 1302–1315.

[14] Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nature Reviews Cancer. 2016; 16: 619–634.

[15] Reckzeh ES, Karageorgis G, Schwalfenberg M, Ceballos J, Nowacki J, Stroet MCM, et al. Inhibition of glucose transporters and glutaminase synergistically impairs tumor cell growth. Cell Chemical Biology. 2019; 26: 1214–1228.e25.

[16] Yu X, Plotnikova O, Bonin PD, Subashi TA, McLellan TJ, Dumlao D, et al. Cryo-EM structures of the human glutamine transporter SLC1A5 (ASCT2) in the outward-facing conformation. eLife. 2019; 8: e48120.

[17] van Geldermalsen M, Wang Q, Nagarajah R, Marshall AD, Thoeng A, Gao D, et al. ASCT2/SLC1a5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer. Oncogene. 2016; 35: 3201–3208.

[18] Toda K, Nishikawa G, Iwamoto M, Itatani Y, Takahashi R, Sakai Y, et al. Clinical role of ASCT2 (SLC1A5) in KRAS-mutated colorectal cancer. International Journal of Molecular Sciences. 2017; 18: 1632.

[19] Crawley O, Giles AC, Desbois M, Kashyap S, Birnbaum R, Grill B. A MIG-15/JNK-1 MAP kinase cascade opposes RPM-1 signaling in synapse formation and learning. PLOS Genetics. 2017; 13: e1007095.

[20] Velho S, Pinto A, Licastro D, Oliveira MJ, Sousa F, Stupka E, et al. Dissecting the signaling pathways associated with the oncogenic activity of MLK3 P252H mutation. BMC Cancer. 2014; 14: 182.

[21] Gadang V, Kohli R, Myronovych A, Hui DY, Perez-Tilve D, Jaeschke A. MLK3 promotes metabolic dysfunction induced by saturated fatty acid-enriched diet. American Journal of Physiology-Endocrinology and Metabolism. 2013; 305: E549–E556.

[22] Lopes C, Pereira C, Medeiros R. ASCT2 and LAT1 contribution to the hallmarks of cancer: from a molecular perspective to clinical translation. Cancers. 2021; 13: 203.

[23] Shen Y, Zhang Y, Li W, Chen K, Xiang M, Ma H. Glutamine metabolism: from proliferating cells to cardiomyocytes. Metabolism. 2021; 121: 154778.

[24] Chen L, Cui H. Targeting glutamine induces apoptosis: a cancer therapy approach. International Journal of Molecular Sciences. 2015; 16: 22830–22855.

[25] Scalise M, Pochini L, Galluccio M, Console L, Indiveri C. Glutamine transport and mitochondrial metabolism in cancer cell growth. Frontiers in Oncology. 2017; 7: 306.

[26] Wang L, Liu Y, Zhao T, Li Z, He J, Zhang B, et al. Topotecan induces apoptosis via ASCT2 mediated oxidative stress in gastric cancer. Phytomedicine. 2019; 57: 117–128.


Abstracted / indexed in

Science Citation Index Expanded (SciSearch) Created as SCI in 1964, Science Citation Index Expanded now indexes over 9,200 of the world’s most impactful journals across 178 scientific disciplines. More than 53 million records and 1.18 billion cited references date back from 1900 to present.

Journal Citation Reports/Science Edition Journal Citation Reports/Science Edition aims to evaluate a journal’s value from multiple perspectives including the journal impact factor, descriptive data about a journal’s open access content as well as contributing authors, and provide readers a transparent and publisher-neutral data & statistics information about the journal.

Directory of Open Access Journals (DOAJ) DOAJ is a unique and extensive index of diverse open access journals from around the world, driven by a growing community, committed to ensuring quality content is freely available online for everyone.

SCImago The SCImago Journal & Country Rank is a publicly available portal that includes the journals and country scientific indicators developed from the information contained in the Scopus® database (Elsevier B.V.)

Publication Forum - JUFO (Federation of Finnish Learned Societies) Publication Forum is a classification of publication channels created by the Finnish scientific community to support the quality assessment of academic research.

Scopus: CiteScore 0.9 (2023) Scopus is Elsevier's abstract and citation database launched in 2004. Scopus covers nearly 36,377 titles (22,794 active titles and 13,583 Inactive titles) from approximately 11,678 publishers, of which 34,346 are peer-reviewed journals in top-level subject fields: life sciences, social sciences, physical sciences and health sciences.

Norwegian Register for Scientific Journals, Series and Publishers Search for publication channels (journals, series and publishers) in the Norwegian Register for Scientific Journals, Series and Publishers to see if they are considered as scientific. (https://kanalregister.hkdir.no/publiseringskanaler/Forside).

Submission Turnaround Time

Conferences

Top