Research progress on relationship between LIMK and colorectal cancer_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

TANG Guo , GAO Xin ,  WEI Shoujiang

Department of Gastrointestinal Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;

Corresponding author：

WEI Shoujiang, Email: nsmcwsj@163.com

Keywords：

LIM kinase; cofilin protein; tumor; inhibitor

DOI：

10.7507/1007-9424.201905051

Video：

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Objective To understand relationship between LIM kinase (LIMK) and colorectal cancer in order to provide research basis for metastasis, invasion, and targeted therapy of colorectal cancer.Method The relevant literatures about the research progress on the structural function of LIMK and its correlation with colorectal cancer in recent years were reviewed.Results The LIMK and its factors in the ROCK/LIMK/cofilin and PAK/LIMK/cofilin pathways were involved in various cell biological behaviors such as the tumor cell cycle progression, tumor cell invasion, migration, and proliferation. For example, the p21-activated kinase 4 (PAK4) participated in the cytoskeletal dynamics to regulate cancer cell migration and invasion through the PAK4/LIMK1/cofilin signaling pathway. The cofilin affected the tumor cell movement and morphology through the Rho/ROCK/LIMK1/cofilin signaling pathway, thus then participated in the tumor cell invasion and migration. In addition, the studies had reported that two tumor metastasis-associated proteins, MYH9 and ACTN4, were the direct targets of LIMK1, and the three interactions could promote the colon cancer progression. Another member of the LIMK family: LIMK2, which inhibited the cell metastasis by limiting the epithelial mesenchymal transition (EMT) process, and the nuclear chain of β-catenin activated the Wnt signaling pathway, leading to the colon cancer progression and metastasis. Diallyl disulfide down-regulated the expression of LIMK1 in the colon cancer cells SW480, inhibited the LIMK1/cofilin signaling pathway, blocked angiogenesis and EMT, and inhibited the colon cancer migration and invasion, while others LIMK inhibitors had not been validated in the colorectal cancer.Conclusions Molecular mechanism of colorectal cancer and its metastasis has not been fully elucidated. Through in-depth study of relationships between colorectal cancer and its metastasis mechanism and LIMK, it could provide a molecular targeted therapeutic breakthrough for colorectal cancer and its metastasis and more help for exploring of diagnosis, recurrence, prognosis and metastasis of colorectal cancer.

Citation： TANG Guo, GAO Xin, WEI Shoujiang. Research progress on relationship between LIMK and colorectal cancer. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2020, 27(2): 252-256. doi: 10.7507/1007-9424.201905051 Copy

1.	Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2.	Chen W, Zheng R, Baade P D, et al. Cancer statistics in China, 2015. Ca Cancer J Clin, 2016, 66(2): 115-132.
3.	Rak R, Kloog Y. Targeting LIM kinase in cancer and neurofibromatosis. Cell Cycle, 2014, 13(9): 1360-1361.
4.	Mardilovich K, Baugh M, Crighton D, et al. LIM kinase inhibitors disrupt mitotic microtubule organization and impair tumor cell proliferation. Oncotarget, 2015, 6(36): 38469-38486.
5.	Prunier C, Josserand V, Vollaire J, et al. LIM kinase inhibitor Pyr1 reduces the growth and metastatic load of breast cancers. Cancer Res, 2016, 76(12): 3541-3552.
6.	Yang N, Higuchi O, Ohashi K, et al. Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature, 1998, 393(6687): 809-812.
7.	Maruta H. Herbal therapeutics that block the oncogenic kinase PAK1: a practical approach towards PAK1-dependent diseases and longevity. Phytother Res, 2014, 28(5): 656-672.
8.	Davila M, Jhala D, Ghosh D, et al. Expression of LIM kinase 1 is associated with reversible G1/S phase arrest, chromosomal instability and prostate cancer. Mol Cancer, 2007, 6: 40.
9.	Vallée B, Cuberos H, Doudeau M, et al. LIMK2-1, a new isoform of human LIMK2, regulates actin cytoskeleton remodeling via a different signaling pathway than that of its two homologs, LIMK2a and LIMK2b. Biochem J, 2018, 475(23): 3745-3761.
10.	Shahi P, Wang CY, Chou J, et al. GATA3 targets semaphorin 3B in mammary epithelial cells to suppress breast cancer progression and metastasis. Oncogene, 2017, 36(40): 5567-5575.
11.	Meyer-Lindenberg A, Mervis CB, Sarpal D, et al. Functional, structural, and metabolic abnormalities of the hippocampal formation in Williams syndrome. J Clin Invest, 2005, 115(7): 1888-1895.
12.	Chen S, Auletta T, Dovirak O, et al. Copy number alterations in pancreatic cancer identify recurrent PAK4 amplification. Cancer Biol Ther, 2008, 7(11): 1793-1802.
13.	Hao C, Huang W, Li X, et al. Development of 2,4-diaminoquinazoline derivatives as potent PAK4 inhibitors by the core refinement strategy. Eur J Med Chem, 2017, 131: 1-13.
14.	Cai S, Ye Z, Wang X, et al. Overexpression of P21-activated kinase 4 is associated with poor prognosis in non-small cell lung cancer and promotes migration and invasion. J Exp Clin Cancer Res, 2015, 34: 48.
15.	Rudolph J, Crawford JJ, Hoeflich KP, et al. Inhibitors of p21-activated kinases (PAKs). J Med Chem, 2015, 58(1): 111-129.
16.	Li D, Zhang Y, Li Z, et al. Activated Pak4 expression correlates with poor prognosis in human gastric cancer patients. Tumour Biol, 2015, 36(12): 9431-9436.
17.	Kidera Y, Tsubaki M, Yamazoe Y, et al. Reduction of lung metastasis, cell invasion, and adhesion in mouse melanoma by statin-induced blockade of the Rho/Rho-associated coiled-coil-containing protein kinase pathway. J Exp Clin Cancer Res, 2010, 29: 127.
18.	Yan J, Pan Y1, Zheng X, et al. Comparative study of ROCK1 and ROCK2 in hippocampal spine formation and synaptic function. Neurosci Bull, 2019, 35(4): 649-660.
19.	Zhang Y, Li A, Shi J, et al. Imbalanced LIMK1 and LIMK2 expression leads to human colorectal cancer progression and metastasis via promoting β-catenin nuclear translocation. Cell Death Dis, 2018, 9(7): 749.
20.	Aggelou H, Chadla P, Nikou S, et al. LIMK/cofilin pathway and Slingshot are implicated in human colorectal cancer progression and chemoresistance. Virchows Arch, 2018, 472(5): 727-737.
21.	Lourenço FC, Munro J, Brown J, et al. Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation. Gut, 2014, 63(3): 480-493.
22.	Sousa-Squiavinato ACM, Rocha MR, Barcellos-de-Souza P, et al. Cofilin-1 signaling mediates epithelial-mesenchymal transition by promoting actin cytoskeleton reorganization and cell-cell adhesion regulation in colorectal cancer cells. Biochim Biophys Acta Mol Cell Res, 2019, 1866(3): 418-429.
23.	Frampton M, Houlston RS. Modeling the prevention of colorectal cancer from the combined impact of host and behavioral risk factors. Genet Med, 2017, 19(3): 314-321.
24.	惠鹏, 刘连新, 梁英健. 结直肠癌肝转移的分子机制研究进展. 中国普外基础与临床杂志, 2019, 26(6): 758-763.
25.	Liao Q, Li R, Zhou R, et al. LIM kinase 1 interacts with myosin-9 and alpha-actinin-4 and promotes colorectal cancer progression. Br J Cancer, 2017, 117(4): 563-571.
26.	Su J, Zhou Y, Pan Z, et al. Downregulation of LIMK1-ADF/cofilin by DADS inhibits the migration and invasion of colon cancer. Sci Rep, 2017, 7: 45624.
27.	Min JS, Kim JC, Kim JA, et al. SIRT2 reduces actin polymerization and cell migration through deacetylation and degradation of HSP90. Biochim Biophys Acta Mol Cell Res, 2018, 1865(9): 1230-1238.
28.	Wang W, Yang C, Nie H, et al. LIMK2 acts as an oncogene in bladder cancer and its functional SNP in the microRNA-135a binding site affects bladder cancer risk. Int J Cancer, 2019, 144(6): 1345-1355.
29.	Zhou Y, Su J, Shi L, et al. DADS downregulates the Rac1-ROCK1/PAK1-LIMK1-ADF/cofilin signaling pathway, inhibiting cell migration and invasion. Oncol Rep, 2013, 29(2): 605-612.
30.	Prunier C, Prudent R, Kapur R, et al. LIM kinases: cofilin and beyond. Oncotarget, 2017, 8(25): 41749-41763.
31.	Song S, Li X, Guo J, et al. Design, synthesis and biological evaluation of 1-phenanthryl-tetrahydroisoquinoline derivatives as novel p21-activated kinase 4 (PAK4) inhibitors. Org Biomol Chem, 2015, 13(12): 3803-3818.
32.	Hao C, Li X, Song S, et al. Advances in the 1-phenanthryl-tetrahydroisoquinoline series of PAK4 inhibitors: potent agents restrain tumor cell growth and invasion. Org Biomol Chem, 2016, 14(32): 7676-7690.
33.	Ohashi K, Sampei K, Nakagawa M, et al. Damnacanthal, an effective inhibitor of LIM-kinase, inhibits cell migration and invasion. Mol Biol Cell, 2014, 25(6): 828-840.
34.	Nguyen BC, Taira N, Maruta H, et al. Artepillin C and other herbal PAK1-blockers: Effects on hair cell proliferation and related PAK1-dependent biological function in cell culture. Phytother Res, 2016, 30(1): 120-127.
35.	Song H, Wang Y, Li L, et al. Cucurbitacin E inhibits proliferation and migration of intestinal epithelial cells via activating cofilin. Front Physiol, 2018, 9: 1090.
36.	Sari-Hassoun M, Clement MJ, Hamdi I, et al. Cucurbitacin Ⅰ elicits the formation of actin/phospho-myosin Ⅱ co-aggregates by stimulation of the RhoA/ROCK pathway and inhibition of LIM-kinase. Biochem Pharmacol, 2016, 102: 45-63.
37.	Park JB, Agnihotri S, Golbourn B, et al. Transcriptional profiling of GBM invasion genes identifies effective inhibitors of the LIM kinase-cofilin pathway. Oncotarget, 2014, 5(19): 9382-9395.
38.	Harrison BA, Almstead ZY, Burgoon H, et al. Discovery and development of LX7101, a dual LIM-kinase and ROCK inhibitor for the treatment of glaucoma. ACS Med Chem Lett, 2014, 6(1): 84-88.
39.	Rak R, Haklai R, Elad-Tzfadia G, et al. Novel LIMK2 inhibitor blocks Panc-1 tumor growth in a mouse xenograft model. Oncoscience, 2014, 1(1): 39-48.

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2. Chen W, Zheng R, Baade P D, et al. Cancer statistics in China, 2015. Ca Cancer J Clin, 2016, 66(2): 115-132.
3. Rak R, Kloog Y. Targeting LIM kinase in cancer and neurofibromatosis. Cell Cycle, 2014, 13(9): 1360-1361.
4. Mardilovich K, Baugh M, Crighton D, et al. LIM kinase inhibitors disrupt mitotic microtubule organization and impair tumor cell proliferation. Oncotarget, 2015, 6(36): 38469-38486.
5. Prunier C, Josserand V, Vollaire J, et al. LIM kinase inhibitor Pyr1 reduces the growth and metastatic load of breast cancers. Cancer Res, 2016, 76(12): 3541-3552.
6. Yang N, Higuchi O, Ohashi K, et al. Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature, 1998, 393(6687): 809-812.
7. Maruta H. Herbal therapeutics that block the oncogenic kinase PAK1: a practical approach towards PAK1-dependent diseases and longevity. Phytother Res, 2014, 28(5): 656-672.
8. Davila M, Jhala D, Ghosh D, et al. Expression of LIM kinase 1 is associated with reversible G1/S phase arrest, chromosomal instability and prostate cancer. Mol Cancer, 2007, 6: 40.
9. Vallée B, Cuberos H, Doudeau M, et al. LIMK2-1, a new isoform of human LIMK2, regulates actin cytoskeleton remodeling via a different signaling pathway than that of its two homologs, LIMK2a and LIMK2b. Biochem J, 2018, 475(23): 3745-3761.
10. Shahi P, Wang CY, Chou J, et al. GATA3 targets semaphorin 3B in mammary epithelial cells to suppress breast cancer progression and metastasis. Oncogene, 2017, 36(40): 5567-5575.
11. Meyer-Lindenberg A, Mervis CB, Sarpal D, et al. Functional, structural, and metabolic abnormalities of the hippocampal formation in Williams syndrome. J Clin Invest, 2005, 115(7): 1888-1895.
12. Chen S, Auletta T, Dovirak O, et al. Copy number alterations in pancreatic cancer identify recurrent PAK4 amplification. Cancer Biol Ther, 2008, 7(11): 1793-1802.
13. Hao C, Huang W, Li X, et al. Development of 2,4-diaminoquinazoline derivatives as potent PAK4 inhibitors by the core refinement strategy. Eur J Med Chem, 2017, 131: 1-13.
14. Cai S, Ye Z, Wang X, et al. Overexpression of P21-activated kinase 4 is associated with poor prognosis in non-small cell lung cancer and promotes migration and invasion. J Exp Clin Cancer Res, 2015, 34: 48.
15. Rudolph J, Crawford JJ, Hoeflich KP, et al. Inhibitors of p21-activated kinases (PAKs). J Med Chem, 2015, 58(1): 111-129.
16. Li D, Zhang Y, Li Z, et al. Activated Pak4 expression correlates with poor prognosis in human gastric cancer patients. Tumour Biol, 2015, 36(12): 9431-9436.
17. Kidera Y, Tsubaki M, Yamazoe Y, et al. Reduction of lung metastasis, cell invasion, and adhesion in mouse melanoma by statin-induced blockade of the Rho/Rho-associated coiled-coil-containing protein kinase pathway. J Exp Clin Cancer Res, 2010, 29: 127.
18. Yan J, Pan Y1, Zheng X, et al. Comparative study of ROCK1 and ROCK2 in hippocampal spine formation and synaptic function. Neurosci Bull, 2019, 35(4): 649-660.
19. Zhang Y, Li A, Shi J, et al. Imbalanced LIMK1 and LIMK2 expression leads to human colorectal cancer progression and metastasis via promoting β-catenin nuclear translocation. Cell Death Dis, 2018, 9(7): 749.
20. Aggelou H, Chadla P, Nikou S, et al. LIMK/cofilin pathway and Slingshot are implicated in human colorectal cancer progression and chemoresistance. Virchows Arch, 2018, 472(5): 727-737.
21. Lourenço FC, Munro J, Brown J, et al. Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation. Gut, 2014, 63(3): 480-493.
22. Sousa-Squiavinato ACM, Rocha MR, Barcellos-de-Souza P, et al. Cofilin-1 signaling mediates epithelial-mesenchymal transition by promoting actin cytoskeleton reorganization and cell-cell adhesion regulation in colorectal cancer cells. Biochim Biophys Acta Mol Cell Res, 2019, 1866(3): 418-429.
23. Frampton M, Houlston RS. Modeling the prevention of colorectal cancer from the combined impact of host and behavioral risk factors. Genet Med, 2017, 19(3): 314-321.
24. 惠鹏, 刘连新, 梁英健. 结直肠癌肝转移的分子机制研究进展. 中国普外基础与临床杂志, 2019, 26(6): 758-763.
25. Liao Q, Li R, Zhou R, et al. LIM kinase 1 interacts with myosin-9 and alpha-actinin-4 and promotes colorectal cancer progression. Br J Cancer, 2017, 117(4): 563-571.
26. Su J, Zhou Y, Pan Z, et al. Downregulation of LIMK1-ADF/cofilin by DADS inhibits the migration and invasion of colon cancer. Sci Rep, 2017, 7: 45624.
27. Min JS, Kim JC, Kim JA, et al. SIRT2 reduces actin polymerization and cell migration through deacetylation and degradation of HSP90. Biochim Biophys Acta Mol Cell Res, 2018, 1865(9): 1230-1238.
28. Wang W, Yang C, Nie H, et al. LIMK2 acts as an oncogene in bladder cancer and its functional SNP in the microRNA-135a binding site affects bladder cancer risk. Int J Cancer, 2019, 144(6): 1345-1355.
29. Zhou Y, Su J, Shi L, et al. DADS downregulates the Rac1-ROCK1/PAK1-LIMK1-ADF/cofilin signaling pathway, inhibiting cell migration and invasion. Oncol Rep, 2013, 29(2): 605-612.
30. Prunier C, Prudent R, Kapur R, et al. LIM kinases: cofilin and beyond. Oncotarget, 2017, 8(25): 41749-41763.
31. Song S, Li X, Guo J, et al. Design, synthesis and biological evaluation of 1-phenanthryl-tetrahydroisoquinoline derivatives as novel p21-activated kinase 4 (PAK4) inhibitors. Org Biomol Chem, 2015, 13(12): 3803-3818.
32. Hao C, Li X, Song S, et al. Advances in the 1-phenanthryl-tetrahydroisoquinoline series of PAK4 inhibitors: potent agents restrain tumor cell growth and invasion. Org Biomol Chem, 2016, 14(32): 7676-7690.
33. Ohashi K, Sampei K, Nakagawa M, et al. Damnacanthal, an effective inhibitor of LIM-kinase, inhibits cell migration and invasion. Mol Biol Cell, 2014, 25(6): 828-840.
34. Nguyen BC, Taira N, Maruta H, et al. Artepillin C and other herbal PAK1-blockers: Effects on hair cell proliferation and related PAK1-dependent biological function in cell culture. Phytother Res, 2016, 30(1): 120-127.
35. Song H, Wang Y, Li L, et al. Cucurbitacin E inhibits proliferation and migration of intestinal epithelial cells via activating cofilin. Front Physiol, 2018, 9: 1090.
36. Sari-Hassoun M, Clement MJ, Hamdi I, et al. Cucurbitacin Ⅰ elicits the formation of actin/phospho-myosin Ⅱ co-aggregates by stimulation of the RhoA/ROCK pathway and inhibition of LIM-kinase. Biochem Pharmacol, 2016, 102: 45-63.
37. Park JB, Agnihotri S, Golbourn B, et al. Transcriptional profiling of GBM invasion genes identifies effective inhibitors of the LIM kinase-cofilin pathway. Oncotarget, 2014, 5(19): 9382-9395.
38. Harrison BA, Almstead ZY, Burgoon H, et al. Discovery and development of LX7101, a dual LIM-kinase and ROCK inhibitor for the treatment of glaucoma. ACS Med Chem Lett, 2014, 6(1): 84-88.
39. Rak R, Haklai R, Elad-Tzfadia G, et al. Novel LIMK2 inhibitor blocks Panc-1 tumor growth in a mouse xenograft model. Oncoscience, 2014, 1(1): 39-48.

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