Cathepsin L Promotes Chemresistance to Neuroblastoma by Modulating Serglycin

Overview

Journal Front Pharmacol

Date 2022 Sep 22

PMID 36133820

Authors

Xiaohuan Du

Leyun Ding

Shungen Huang

Fang Li

Yinghui Yan

Ruze Tang

Xinyuan Ding

Zengyan Zhu

Wenjuan Wang

Affiliations

Soon will be listed here.

Abstract

Cathepsin L (CTSL), a lysosomal acid cysteine protease, is found to play a critical role in chemosencitivity and tumor progression. However, the potential roles and molecular mechanisms of CTSL in chemoresistance in neuroblastoma (NB) are still unclear. In this study, the correlation between clinical characteristics, survival and CTSL expression were assessed in Versteeg dataset. The chemoresistant to cisplatin or doxorubicin was detected using CCK-8 assay. Western blot was employed to detect the expression of CTSL, multi-drug resistance proteins, autophagy-related proteins and apoptosis-related proteins in NB cells while knocking down CTSL. Lysosome staining was analyzed to access the expression levels of lysosomes in NB cells. The expression of apoptosis markers was analyzed with immunofluorescence. Various datasets were analyzed to find the potential protein related to CTSL. In addition, a subcutaneous tumor xenografts model in M-NSG mice was used to assess tumor response to CTSL inhibition . Based on the validation dataset (Versteeg), we confirmed that CTSL served as a prognostic marker for poor clinical outcome in NB patients. We further found that the expression level of CTSL was higher in SK-N-BE (2) cells than in IMR-32 cells. Knocking down CTSL reversed the chemoresistance in SK-N-BE (2) cells. Furthermore, combination of CTSL inhibition and chemotherapy potently blocked tumor growth . Mechanistically, CTSL promoted chemoresistance in NB cells by up-regulating multi-drug resistance protein ABCB1 and ABCG2, inhibiting the autophagy level and cell apoptpsis. Furthermore, we observed six datasets and found that Serglycin (SRGN) expression was positively associated with CTSL expresssion. CTSL could mediate chemoresistance by up-regulating SRGN expression in NB cells and SRGN expression was positively correlated with poor prognosis of NB patients. Taken together, our findings indicate that the CTSL promotes chemoresistance to cisplatin and doxorubicin by up-regulating the expression of multi-drug resistance proteins and inhibiting the autophagy level and cell apoptosis in NB cells. Thus, CTSL may be a therapeutic target for overcoming chemoresistant to cisplatin and doxorubicin in NB patients.

Citing Articles

CTSL Promotes Autophagy in Laryngeal Cancer Through the IL6-JAK-STAT3 Signalling Pathway.

Wang X, Wang J, Wang L, Song M, Meng H, Guo E J Cell Mol Med. 2025; 29(3):e70364.

PMID: 39893643 PMC: 11787816. DOI: 10.1111/jcmm.70364.

Therapy resistance in neuroblastoma: Mechanisms and reversal strategies.

Zhou X, Wang X, Li N, Guo Y, Yang X, Lei Y Front Pharmacol. 2023; 14:1114295.

PMID: 36874032 PMC: 9978534. DOI: 10.3389/fphar.2023.1114295.

References

Guo J, Chiu C, Wang M, Li F, Chen J . Proteoglycan serglycin promotes non-small cell lung cancer cell migration through the interaction of its glycosaminoglycans with CD44. J Biomed Sci. 2020; 27(1):2. PMC: 6939340. DOI: 10.1186/s12929-019-0600-3. View

Wang L, Zhao Y, Xiong Y, Wang W, Fei Y, Tan C . K-ras mutation promotes ionizing radiation-induced invasion and migration of lung cancer in part via the Cathepsin L/CUX1 pathway. Exp Cell Res. 2017; 362(2):424-435. DOI: 10.1016/j.yexcr.2017.12.006. View

Sudhan D, Siemann D . Cathepsin L targeting in cancer treatment. Pharmacol Ther. 2015; 155:105-16. PMC: 4624022. DOI: 10.1016/j.pharmthera.2015.08.007. View

Zhang Z, Deng Y, Zheng G, Jia X, Xiong Y, Luo K . SRGN-TGFβ2 regulatory loop confers invasion and metastasis in triple-negative breast cancer. Oncogenesis. 2017; 6(7):e360. PMC: 5541705. DOI: 10.1038/oncsis.2017.53. View

Davidson S, Vander Heiden M . Critical Functions of the Lysosome in Cancer Biology. Annu Rev Pharmacol Toxicol. 2016; 57:481-507. DOI: 10.1146/annurev-pharmtox-010715-103101. View

Yang C, Wang X . Lysosome biogenesis: Regulation and functions. J Cell Biol. 2021; 220(6). PMC: 8105738. DOI: 10.1083/jcb.202102001. View

Gao J, Wang W . Knockdown of galectin-1 facilitated cisplatin sensitivity by inhibiting autophagy in neuroblastoma cells. Chem Biol Interact. 2018; 297:50-56. DOI: 10.1016/j.cbi.2018.10.014. View

Li X, Qian X, Lu Z . Local histone acetylation by ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Autophagy. 2017; 13(10):1790-1791. PMC: 5640193. DOI: 10.1080/15548627.2017.1349581. View

Tolbert V, Matthay K . Neuroblastoma: clinical and biological approach to risk stratification and treatment. Cell Tissue Res. 2018; 372(2):195-209. PMC: 5918153. DOI: 10.1007/s00441-018-2821-2. View

10.

Cui F, Wang W, Wu D, He X, Wu J, Wang M . Overexpression of Cathepsin L is associated with gefitinib resistance in non-small cell lung cancer. Clin Transl Oncol. 2015; 18(7):722-7. DOI: 10.1007/s12094-015-1424-6. View

11.

Han M, Zhao Y, Tan C, Xiong Y, Wang W, Wu F . Cathepsin L upregulation-induced EMT phenotype is associated with the acquisition of cisplatin or paclitaxel resistance in A549 cells. Acta Pharmacol Sin. 2016; 37(12):1606-1622. PMC: 5309731. DOI: 10.1038/aps.2016.93. View

12.

Mao Z, Sang M, Chen C, Zhu W, Gong Y, Pei D . CSN6 Promotes the Migration and Invasion of Cervical Cancer Cells by Inhibiting Autophagic Degradation of Cathepsin L. Int J Biol Sci. 2019; 15(6):1310-1324. PMC: 6567803. DOI: 10.7150/ijbs.32987. View

13.

Parigiani M, Ketscher A, Timme S, Bronsert P, Schlimpert M, Kammerer B . Conditional Gene Targeting Reveals Cell Type-Specific Roles of the Lysosomal Protease Cathepsin L in Mammary Tumor Progression. Cancers (Basel). 2020; 12(8). PMC: 7463523. DOI: 10.3390/cancers12082004. View

14.

Mijanovic O, Brankovic A, Panin A, Savchuk S, Timashev P, Ulasov I . Cathepsin B: A sellsword of cancer progression. Cancer Lett. 2019; 449:207-214. PMC: 6488514. DOI: 10.1016/j.canlet.2019.02.035. View

15.

Zhang Z, Qiu N, Yin J, Zhang J, Liu H, Guo W . SRGN crosstalks with YAP to maintain chemoresistance and stemness in breast cancer cells by modulating HDAC2 expression. Theranostics. 2020; 10(10):4290-4307. PMC: 7150493. DOI: 10.7150/thno.41008. View

16.

Zhang H, Zhang L, Wei L, Gao X, Tang L, Gong W . Knockdown of cathepsin L sensitizes ovarian cancer cells to chemotherapy. Oncol Lett. 2016; 11(6):4235-4239. PMC: 4888267. DOI: 10.3892/ol.2016.4494. View

17.

Wang W, Xiong Y, Ding X, Wang L, Zhao Y, Fei Y . Cathepsin L activated by mutant p53 and Egr-1 promotes ionizing radiation-induced EMT in human NSCLC. J Exp Clin Cancer Res. 2019; 38(1):61. PMC: 6367810. DOI: 10.1186/s13046-019-1054-x. View

18.

Gu Y, Lv F, Xue M, Chen K, Cheng C, Ding X . The deubiquitinating enzyme UCHL1 is a favorable prognostic marker in neuroblastoma as it promotes neuronal differentiation. J Exp Clin Cancer Res. 2018; 37(1):258. PMC: 6203192. DOI: 10.1186/s13046-018-0931-z. View

19.

Zafar A, Wang W, Liu G, Wang X, Xian W, McKeon F . Molecular targeting therapies for neuroblastoma: Progress and challenges. Med Res Rev. 2020; 41(2):961-1021. PMC: 7906923. DOI: 10.1002/med.21750. View

20.

Zhang H, Zhang J, Li C, Xu H, Dong R, Chen C . Survival Association and Cell Cycle Effects of B7H3 in Neuroblastoma. J Korean Neurosurg Soc. 2020; 63(6):707-716. PMC: 7671786. DOI: 10.3340/jkns.2019.0255. View