Biomolecules & Therapeutics

  • 제31권3호
  • /
  • Pages.330-339
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  • 2023
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  • 1976-9148(pISSN)
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  • 2005-4483(eISSN)
한국응용약물학회 (The Korean Society of Applied Pharmacology)
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Liver Kinase B1 Mediates Its Anti-Tumor Function by Binding to the N-Terminus of Malic Enzyme 3

  • Seung Bae Rho (Division of Cancer Biology, Research Institute, National Cancer Center) ;
  • Hyun Jung Byun (College of Pharmacy, Dongguk University) ;
  • Boh-Ram Kim (College of Pharmacy, Dongguk University) ;
  • Chang Hoon Lee (College of Pharmacy, Dongguk University)
  • 투고 : 2023.03.01
  • 심사 : 2023.03.24
  • 발행 : 2023.05.01
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⟨ 이전 논문 다음 논문 ⟩

초록

Liver kinase B1 (LKB1) is a crucial tumor suppressor involved in various cellular processes, including embryonic development, tumor initiation and progression, cell adhesion, apoptosis, and metabolism. However, the precise mechanisms underlying its functions remain elusive. In this study, we demonstrate that LKB1 interacts directly with malic enzyme 3 (ME3) through the N-terminus of the enzyme and identified the binding regions necessary for this interaction. The binding activity was confirmed to promote the expression of ME3 in an LKB1-dependent manner and was also shown to induce apoptosis activity. Furthermore, LKB1 and ME3 overexpression upregulated the expression of tumour suppressor proteins (p53 and p21) and downregulated the expression of antiapoptotic proteins (nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and B-cell lymphoma 2 (Bcl-2)). Additionally, LKB1 and ME3 enhanced the transcription of p21 and p53 and inhibited the transcription of NF-κB. Moreover, LKB1 and ME3 suppressed the phosphorylation of various components of the phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B signaling pathway. Overall, these results suggest that LKB1 promotes pro-apoptotic activities by inducing ME3 expression.

키워드

과제정보

This work was supported by a grant from the National Cancer Center, Korea (NCC-2112500-1 and 2210450-1) and the Basic Science Research Program and the BK21 FOUR program through the NRF (NRF-2018R1A5A2023127, and NRF-2020R1A2C3004973).

참고문헌

  1. Alessi, D. R., Sakamoto, K. and Bayascas, J. R. (2006) LKB1-dependent signaling pathways. Annu. Rev. Biochem. 75, 137-163. https://doi.org/10.1146/annurev.biochem.75.103004.142702
  2. Aviles-Salas, A., Diaz-Garcia, D. A., Lara-Mejia, L., Cardona, A. F., Orozco-Morales, M., Catalan, R., Hernandez-Pedro, N. Y., Rios-Garcia, E., Ramos-Ramirez, M. and Arrieta, O. (2023) LKB1 loss assessed by immunohistochemistry as a prognostic marker to firstline therapy in advanced non-small-cell lung cancer. Curr. Oncol. 30, 333-343.
  3. Bhatt, V., Lan, T., Wang, W., Kong, J., Lopes, E. C., Wang, J., Khayati, K., Raju, A., Rangel, M., Lopez, E., Hu, Z. S., Luo, X., Su, X., Malhotra, J., Hu, W., Pine, S.,R., White, E. and Guo, J. Y. (2023) Inhibition of autophagy and MEK promotes ferroptosis in Lkb1-deficient Kras-driven lung tumors. Cell Death & Disease 14, 61.
  4. Chang, G. G. and Tong, L. (2003) Structure and function of malic enzymes, a new class of oxidative decarboxylases. Biochemistry 42, 12721-12733. https://doi.org/10.1021/bi035251+
  5. Cheng, C. P., Huang, L. C., Chang, Y. L., Hsieh, C. H., Huang, S. M. and Hueng, D. Y. (2016) The mechanisms of malic enzyme 2 in the tumorigenesis of human gliomas. Oncotarget 7, 41460.
  6. Costa Rosa, L. F. B. P., Curi, R., Murphy, C. and Newsholme, P. (1995) Effect of adrenaline and phorbol myristate acetate or bacterial lipopolysaccharide on stimulation of pathways of macrophage glucose, glutamine and O2 metabolism. Evidence for cyclic AMP-dependent protein kinase mediated inhibition of glucose-6-phosphate dehydrogenase and activation of NADP+-dependent 'malic' enzyme. Biochem. J. 310, 709-714. https://doi.org/10.1042/bj3100709
  7. Dmitriev, L. (2001) Activity of key enzymes in microsomal and mitochondrial membranes depends on the redox reactions involving lipid radicals. Membr. Cell Biol. 14, 649-662.
  8. Gao, Y., Xiao, Q., Ma, H., Li, L., Liu, J., Feng, Y., Fang, Z., Wu, J., Han, X., Zhang, J., Sun, Y., Wu, G., Padera, R., Chen, H., Wong, K. K., Ge, G. and Ji, H. (2010) LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling. Proc Natl Acad Sci USA 107, 18892-18897. https://doi.org/10.1073/pnas.1004952107
  9. Guertin, D. A. and Sabatini, D. M. (2005) An expanding role for mTOR in cancer. Trends Mol. Med. 11, 353-361. https://doi.org/10.1016/j.molmed.2005.06.007
  10. Gurumurthy, S., Xie, S. Z., Alagesan, B., Kim, J., Yusuf, R. Z., Saez, B., Tzatsos, A., Ozsolak, F., Milos, P., Ferrari, F., Park, P. J., Shirihai, O. S., Scadden, D. T. and Bardeesy, N. (2010) The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468, 659-663. https://doi.org/10.1038/nature09572
  11. Hardie, D. G., Ross, F. A. and Hawley, S. A. (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13, 251-262. https://doi.org/10.1038/nrm3311
  12. Hardie, D. G. (2013) The LKB1-AMPK pathway-friend or foe in cancer? Cancer Cell 23, 131-132. https://doi.org/10.1016/j.ccr.2013.01.009
  13. Hasan, N. M., Longacre, M. J., Stoker, S. W., Kendrick, M. A. and MacDonald, M. J. (2015) Mitochondrial malic enzyme 3 is important for insulin secretion in pancreatic β-cells. Mol. Endocrinol. 29, 396-410. https://doi.org/10.1210/me.2014-1249
  14. Huynh, M. K. Q., Kinyua, A. W., Yang, D. J. and Kim, K. W. (2016) Hypothalamic AMPK as a regulator of energy homeostasis. Neural Plast. 2016, 2754078.
  15. Infante, J. P. and Huszagh, V. A. (1998) Analysis of the putative role of 24-carbon polyunsaturated fatty acids in the biosynthesis of docosapentaenoic (22:5n-6) and docosahexaenoic (22:6n-3) acids. FEBS Lett. 431, 1-6. https://doi.org/10.1016/S0014-5793(98)00720-0
  16. Ishigami, S. I., Arii, S., Furutani, M., Niwano, M., Harada, T., Mizumoto, M., Mori, A., Onodera, H. and Imamura, M. (1998) Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer. Br J Cancer 78, 1379-1384. https://doi.org/10.1038/bjc.1998.688
  17. Jeon, S. M. (2016) Regulation and function of AMPK in physiology and diseases. Exp. Mol. Med. 48, e245-e245. https://doi.org/10.1038/emm.2016.81
  18. Jiang, B. H. and Liu, L. Z. (2008) AKT signaling in regulating angiogenesis. Curr Cancer Drug Targets 8, 19-26. https://doi.org/10.2174/156800908783497122
  19. Kang, G. J., Park, J. H., Kim, H. J., Kim, E. J., Kim, B., Byun, H. J., Yu, L., Nguyen, T. M., Nguyen, T. H., Kim, K. S., Huy, H. P., Rahman, M., Kim, Y. H., Jang, J. Y., Park, M. K., Lee, H., Choi, C. I., Lee, K., Han, H. K., Cho, J., Rho, S. B. and Lee, C. H. (2022) PRR16/Largen induces epithelial-mesenchymal transition through the interaction with ABI2 leading to the activation of ABL1 kinase. Biomol. Ther. (Seoul) 30, 340-347. https://doi.org/10.4062/biomolther.2022.066
  20. Katipally, R. R., Spurr, L. F., Gutiontov, S.I., Turchan, W. T., Connell, P., Juloori, A., Malik, R., Binkley. M. S., Jiang, A. L., Rouhani, S. J., Chervin, C. S., Wanjari, P., Segal, J. P., Ng, V., Loo, B. W., Gomez, D. R., Bestvina, C. M., Vokes, E. E., Ferguson, M. K., Donington, J. S., Diehn, M. and Pitroda, S. P. (2023) STK11 Inactivation Predicts Rapid Recurrence in Inoperable Early-Stage Non-Small-Cell Lung Cancer. JCO Precision Oncol. 7, e2200273.
  21. Konen, J., Wilkinson, S., Lee, B., Fu, H., Zhou, W., Jiang, Y. and Marcus, A. I. (2016) LKB1 kinase-dependent and-independent defects disrupt polarity and adhesion signaling to drive collagen remodeling during invasion. Mol. Biol. Cell 27, 1069-1084. https://doi.org/10.1091/mbc.E15-08-0569
  22. Liang, J., Shao, S. H., Xu, Z.-X., Hennessy, B., Ding, Z., Larrea, M., Kondo, S., Dumont, D. J., Gutterman, J. U., Walker, C. L., Slingerland, J. M. and Mills, G. B. (2007) The energy sensing LKB1-AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosis. Nat. Cell Biol. 9, 218-224. https://doi.org/10.1038/ncb1537
  23. Liu, T., Qin, W., Hou, L. and Huang, Y. (2015) MicroRNA-17 promotes normal ovarian cancer cells to cancer stem cells development via suppression of the LKB1-p53-p21/WAF1 pathway. Tumor Biol. 36, 1881-1893. https://doi.org/10.1007/s13277-014-2790-3
  24. Marignani, P. A., Kanai, F. and Carpenter, C. L. (2001) LKB1 associates with Brg1 and is necessary for Brg1-induced growth arrest. J. Biol. Chem. 276, 32415-32418. https://doi.org/10.1074/jbc.C100207200
  25. Ma, X. M. and Blenis, J. (2009) Molecular mechanisms of mTOR-mediated translational control. Nat. Rev. Mol. Cell Biol. 10, 307-318. https://doi.org/10.1038/nrm2672
  26. Mehenni, H., Lin-Marq, N., Buchet-Poyau, K., Reymond, A., Collart, M. A., Picard, D. and Antonarakis, S. E. (2005) LKB1 interacts with and phosphorylates PTEN: a functional link between two proteins involved in cancer predisposing syndromes. Hum. Mol. Genet. 14, 2209-2219. https://doi.org/10.1093/hmg/ddi225
  27. Men, Y., Zhang, A., Li, H., Jin, Y., Sun, X., Li, H. and Gao, J. (2015) LKB1 regulates cerebellar development by controlling sonic hedgehog-mediated granule cell precursor proliferation and granule cell migration. Sci. Rep. 5, 16232.
  28. Mihaylova, M. M. and Shaw, R. J. (2011) The AMPK signalling path-way coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 13, 1016-1023. https://doi.org/10.1038/ncb2329
  29. Oakhill, J. S., Scott, J. W. and Kemp, B. E. (2012) AMPK functions as an adenylate charge-regulated protein kinase. Trends Endocrinol. Metab. 23, 125-132. https://doi.org/10.1016/j.tem.2011.12.006
  30. Omori, Y., Ono, Y., Morikawa, T., Motoi, F., Higuchi, R., Yamamoto, M., Hayakawa, Y., Karasaki, H., Mizukami, Y., Unno, M. and Furukawa, T. (2023) Serine/Threonine Kinase 11 plays a canonical role in malignant progression of KRAS-mutant and GNAS-wild-type intraductal papillary mucinous neoplasms of the pancreas. Ann. Surg. 277, e384-e395. https://doi.org/10.1097/SLA.0000000000004842
  31. Partanen, J. I., Nieminen, A. I., Makela, T. P. and Klefstrom, J. (2007) Suppression of oncogenic properties of c-Myc by LKB1-controlled epithelial organization. Proc. Natl. Acad. Sci. U. S. A. 104, 14694-14699. https://doi.org/10.1073/pnas.0704677104
  32. Ren, J.-G., Seth, P., Clish, C. B., Lorkiewicz, P. K., Higashi, R. M., Lane, A. N., Fan, T. W.-M. and Sukhatme, V. P. (2014) Knockdown of malic enzyme 2 suppresses lung tumor growth, induces differentiation and impacts PI3K/AKT signaling. Sci. Rep. 4, 5414.
  33. Ren, J.-G., Seth, P., Everett, P., Clish, C. B. and Sukhatme, V. P. (2010) Induction of erythroid differentiation in human erythroleukemia cells by depletion of malic enzyme 2. PLoS One 5, e12520.
  34. Rho, S. B., Lee, S. H., Byun, H. J., Kim, B. R. and Lee, C. H. (2020) IRF-1 inhibits angiogenic activity of HPV16 E6 oncoprotein in cervical cancer. Int. J. Mol. Sci. 21, 7622.
  35. Rho, S. B., Byun, H. J., Kim, B. R. and Lee, C. H. (2021) Knockdown of LKB1 sensitizes endometrial cancer cells via AMPK activation. Biomol. Ther. 29, 650.
  36. Rho, S. B., Byun, H.-J., Kim, B.-R. and Lee, C. H. (2022) Snail promotes cancer cell proliferation via its interaction with the BIRC3. Biomol. Ther. (Seoul) 30, 380-388. https://doi.org/10.4062/biomolther.2022.063
  37. Rho, S. B., Kim, B.-R. and Kang, S. (2011) A gene signature-based approach identifies thioridazine as an inhibitor of phosphatidylinositol-3'-kinase (PI3K)/AKT pathway in ovarian cancer cells. Gynecol. Oncol. 120, 121-127. https://doi.org/10.1016/j.ygyno.2010.10.003
  38. Rho, S. B., Lee, K. W., Lee, S.-H., Byun, H. J., Kim, B.-R. and Lee, C. H. (2021) Novel anti-angiogenic and anti-tumour activities of the N-terminal domain of NOEY2 via binding to VEGFR-2 in ovarian cancer. Biomol. Ther. (Seoul) 29, 506-518. https://doi.org/10.4062/biomolther.2021.121
  39. Rossi, D. J., Ylikorkala, A., Korsisaari, N., Salovaara, R., Luukko, K., Launonen, V., Henkemeyer, M., Ristimaki, A., Aaltonen, L. A. and Makela, T. P. (2002) Induction of cyclooxygenase-2 in a mouse model of Peutz-Jeghers polyposis. Proc. Natl. Acad. Sci. U. S. A. 99, 12327-12332. https://doi.org/10.1073/pnas.192301399
  40. Saxton, R. A. and Sabatini, D. M. (2017) mTOR signaling in growth, metabolism, and disease. Cell 168, 960-976. https://doi.org/10.1016/j.cell.2017.02.004
  41. Scott, K. D., Nath-Sain, S., Agnew, M. D. and Marignani, P. A. (2007) LKB1 catalytically deficient mutants enhance cyclin D1 expression. Cancer Res. 67, 5622-5627. https://doi.org/10.1158/0008-5472.CAN-07-0762
  42. Shackelford, D. B. and Shaw, R. J. (2009) The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat. Rev. Cancer 9, 563-575. https://doi.org/10.1038/nrc2676
  43. Steinberg, G. R. and Kemp, B. E. (2009) AMPK in health and disease. Physiological. Rev. 89, 1025-1078. https://doi.org/10.1152/physrev.00011.2008
  44. Sun, Y., Li, Z. and Song, K. (2021) AR-mTOR-SRF axis regulates HMMR expression in human prostate cancer cells. Biomol. Ther. (Seoul) 29, 667-677. https://doi.org/10.4062/biomolther.2021.040
  45. Tahmatzopoulos, A., Rowland, R. G. and Kyprianou, N. (2004) The role of α-blockers in the management of prostate cancer. Expert Opin Pharmacother 5, 1279-1285. https://doi.org/10.1517/14656566.5.6.1279
  46. Tanwar, P. S., Mohapatra, G., Chiang, S., Engler, D. A., Zhang, L., Kaneko-Tarui, T., Ohguchi Y., Birrer, M. J. and Teixeira, J. M. (2014) Loss of LKB1 and PTEN tumor suppressor genes in the ovarian surface epithelium induces papillary serous ovarian cancer. Carcinogenesis 35, 546-553. https://doi.org/10.1093/carcin/bgt357
  47. Tiainen, M., Vaahtomeri, K., Ylikorkala, A. and Makela, T. P. (2002) Growth arrest by the LKB1 tumor suppressor: induction of p21WAF1/CIP1. Hum. Mol. Genet. 11, 1497-1504. https://doi.org/10.1093/hmg/11.13.1497
  48. Wang, Y., Li, N., Jiang, W., Deng, W., Ye, R., Xu, C., Qiao, Y., Sharma, A., Zhang, M., Hung, M. C. and Lin, S. H. (2018) Mutant LKB1 confers enhanced radiosensitization in combination with trametinib in KRAS-mutant non-small cell lung cancer. Clin. Cancer Res. 24, 5744-5756. https://doi.org/10.1158/1078-0432.CCR-18-1489
  49. Wang, Y. P., Sharda, A., Xu, S. N., Van Gastel, N., Man, C. H., Choi, U., Leong, W. Z., Li, X. and Scadden, D. T. (2021) Malic enzyme 2 connects the Krebs cycle intermediate fumarate to mitochondrial biogenesis. Cell Metabol. 33, 1027-1041.e8. https://doi.org/10.1016/j.cmet.2021.03.003
  50. Wei, S., LiVolsi, V. A., Brose, M. S., Montone, K. T., Morrissette, J. J. and Baloch, Z. W. (2016) STK11 mutation identified in thyroid carcinoma. Endocrine Pathol. 27, 65-69. https://doi.org/10.1007/s12022-015-9411-6
  51. Wen, D., Liu, D., Tang, J., Dong, L., Liu, Y., Tao, Z., Wan, J., Gao, D., Wang, L., Sun, H., Fan, J. and Wu, W. (2015) Malic enzyme 1 induces epithelial-mesenchymal transition and indicates poor prognosis in hepatocellular carcinoma. Tumor Biol. 36, 6211-6221. https://doi.org/10.1007/s13277-015-3306-5
  52. Wingo, S. N., Gallardo, T. D., Akbay, E. A., Liang, M. C., Contreras, C. M., Boren, T., .Shimamura, T., ,Miller, D. S., , Sharpless, N. E., Bardeesy, N., Kwiatkowski, D.J., Schorge, J.O., Wong K. and Castrillon, D. H. (2009) Somatic LKB1 mutations promote cervical cancer progression. PloS one, 4, e5137.
  53. Yang, Z., Lanks, C. W. and Tong, L. (2002) Molecular mechanism for the regulation of human mitochondrial NAD (P)+-dependent malic enzyme by ATP and fumarate. Structure 10, 951-960. https://doi.org/10.1016/S0969-2126(02)00788-8
  54. Zagorska, A., Deak, M., Campbell, D. G., Banerjee, S., Hirano, M., Aizawa, S., Prescott, A. R. and Alessi, D. R. (2010) New roles for the LKB1-NUAK pathway in controlling myosin phosphatase complexes and cell adhesion. Sci. Signal. 3, ra25.
  55. Zhang, W., Wang, Q., Song, P. and Zou, M.-H. (2013) Liver kinase b1 is required for white adipose tissue growth and differentiation. Diabetes 62, 2347-2358. https://doi.org/10.2337/db12-1229
  56. Zhang, Y., Shi, J., Luo, J., Liu, C. and Zhu, L. (2023) Metabolic heterogeneity in early-stage lung adenocarcinoma revealed by RNA-seq and scRNA-seq. Clin Transl Oncol. 1-12.
  57. Zhao, R.-X. and Xu, Z.-X. (2014) Targeting the LKB1 tumor suppressor. Curr. Drug Targets 15, 32-52. https://doi.org/10.2174/1389450114666140106095811