Doxorubicin induces de novo expression of N-terminal-truncated matrix metalloproteinase-2 in cardiac myocytes

Chan, Brandon; Roczkowsky, Andrej; Moser, Nils; Poirier, Mathieu; Hughes, Bryan; Ilarraza, Ramses; Schulz, Richard

doi:10.1139/cjpp-2018-0275

Cited by 15 publications

(15 citation statements)

References 43 publications

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“…For instance, a study by Mohammed et al investigated the impact of a sublethal concentration of doxorubicin on several cancer cell lines, revealing that sublethal concentrations enhances cell migration and invasion through SFK activation in both non‐invasive and invasive cancer cell lines, including U2OS 23 . Furthermore, doxorubicin has been reported to increase the expression of MMP‐2 and MMP‐9 in cardiac myocytes 11,24 . These findings align with the study by Mohammed et al, as a sublethal concentration of doxorubicin activates SFKs, augmenting the expression of MMP‐2, and consequently, enhancing cell migration 23 …”

Section: Introductionsupporting

confidence: 71%

MMP‐2 regulates Src activation via repression of the CHK/MATK tumor suppressor in osteosarcoma

Maybee,

Cromwell,

Hubbard

et al. 2023

Cancer Reports

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BackgroundDoxorubicin, a first‐line anticancer drug for osteosarcoma treatment, has been the subject of recent research exploring the mechanisms behind its chemoresistance and its ability to enhance cell migration at sublethal concentrations. Matrix metalloproteinase‐2 (MMP‐2), a type IV collagenase and zinc‐dependent endopeptidase, is well‐known for degrading the extracellular matrix and promoting cancer metastasis. Our previous work demonstrated that nuclear MMP‐2 regulates ribosomal RNA transcription via histone clipping, thereby controlling gene expression. Additionally, MMP‐2 activity is regulated by the non‐receptor tyrosine kinase and oncogene, Src, which plays a crucial role in cell adhesion, invasion, and metastasis. Src kinase is primarily regulated by two endogenous inhibitors: C‐terminal Src kinase (Csk) and Csk homologous kinase (CHK/MATK).AimIn this study, we reveal that the MMP‐2 gene acts as an upstream regulator of Src kinase activity by suppressing its endogenous inhibitor, CHK/MATK, in osteosarcoma cells.Methods and ResultsWe show that enhanced osteosarcoma cell migration which is induced by sublethal concentrations of doxorubicin can be overcome by inactivating the MMP‐2 gene or overexpressing CHK/MATK. Our findings highlight the MMP‐2 gene as a promising additional target for combating cancer cell migration and metastasis. This is due to its role in suppressing on the gene and protein expression of the tumor suppressor CHK/MATK in osteosarcoma.ConclusionBy targeting the MMP‐2 gene, we can potentially enhance the effectiveness of doxorubicin treatment and reduce chemoresistance in osteosarcoma.

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Section: Introductionsupporting

confidence: 71%

MMP‐2 regulates Src activation via repression of the CHK/MATK tumor suppressor in osteosarcoma

Maybee,

Cromwell,

Hubbard

et al. 2023

Cancer Reports

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“…In a DOX-induced cardiotoxicity study, Polegato et al (2015) showed that DOX partially increased MMP-2 activity. Chan et al (2018) reported that DOX increased MMP-2 activity and levels in cardiomyocytes. In their DOX-induced toxicity study performed using Western blotting, they also found that DOX increased MMP-2 levels and decreased TIMP2 levels.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the protective effects of curcumin and caffeic acid phenethyl ester against doxorubicin‐induced testicular toxicity

et al. 2020

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Testicular dysfunction is one of the serious side effects of cytotoxic chemotherapy. It has been reported that low sexual function and quality of life and infertility concerns associated with gonadal insufficiency in young patients are related to psychosocial distress (Levi et al., 2015). Doxorubicin (DOX, brand name Adriamycin), which is one of the most important cornerstones of many chemotherapeutic protocols, is an anticancer drug selected in the treatment of many chemo-responsive tumours from ovarian, breast, liver and lung cancer and lymphomas. However, DOX can cause severe dose-dependent toxicity for other nontarget tissues, including testicular tissues (e.g. reduced testicular weight; Nishi et al., 2018). Studies have reported that DOX toxicity causes testicular damage and apoptosis and adversely affects reproductive function (Kopalli et al., 2016; Nowrouzi et al., 2019). In addition, DOX has been reported to increase oxidative stress by reducing antioxidant capacity in testicular tissue (Uyeturk et al., 2014). Does DOX cause testicular toxicity by only increasing oxidative stress and apoptosis? Or does DOX have an effect on testicular

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“…In addition, MMP-9 overexpression has also been correlated with poor prognosis in colon, gastric, lung, and pancreatic cancers [83]. Dox has been reported to induce MMP-2 and MMP-9 in cardiac myocytes via MAP kinase pathway as well as through AP-1 pathway in oxidative stress [84,85]. MMP-14 is a crucial player in active cellular invasion.…”

Section: Discussionmentioning

confidence: 99%

Sublethal doxorubicin promotes migration and invasion of breast cancer cells: role of Src Family non-receptor tyrosine kinases

et al. 2021

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Background Doxorubicin (Dox) is a widely used chemotherapy, but its effectiveness is limited by dose-dependent side effects. Although lower Dox doses reduce this risk, studies have reported higher recurrence of local disease with no improvement in survival rate in patients receiving low doses of Dox. To effectively mitigate this, a better understanding of the adverse effects of suboptimal Dox doses is needed. Methods Effects of sublethal dose of Dox on phenotypic changes were assessed with light and confocal microscopy. Migratory and invasive behavior were assessed by wound healing and transwell migration assays. MTT and LDH release assays were used to analyze cell growth and cytotoxicity. Flow cytometry was employed to detect cell surface markers of cancer stem cell population. Expression and activity of matrix metalloproteinases were probed with qRT-PCR and zymogen assay. To identify pathways affected by sublethal dose of Dox, exploratory RNAseq was performed and results were verified by qRT-PCR in multiple cell lines (MCF7, ZR75-1 and U-2OS). Regulation of Src Family kinases (SFK) by key players in DNA damage response was assessed by siRNA knockdown along with western blot and qRT-PCR. Dasatinib and siRNA for Fyn and Yes was employed to inhibit SFKs and verify their role in increased migration and invasion in MCF7 cells treated with sublethal doses of Dox. Results The results show that sublethal Dox treatment leads to increased migration and invasion in otherwise non-invasive MCF7 breast cancer cells. Mechanistically, these effects were independent of the epithelial mesenchymal transition, were not due to increased cancer stem cell population, and were not observed with other chemotherapies. Instead, sublethal Dox induces expression of multiple SFK—including Fyn, Yes, and Src—partly in a p53 and ATR-dependent manner. These effects were validated in multiple cell lines. Functionally, inhibiting SFKs with Dasatinib and specific downregulation of Fyn suppressed Dox-induced migration and invasion of MCF7 cells. Conclusions Overall, this study demonstrates that sublethal doses of Dox activate a pro-invasive, pro-migration program in cancer cells. Furthermore, by identifying SFKs as key mediators of these effects, our results define a potential therapeutic strategy to mitigate local invasion through co-treatment with Dasatinib.

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Doxorubicin induces de novo expression of N-terminal-truncated matrix metalloproteinase-2 in cardiac myocytes

Cited by 15 publications

References 43 publications

MMP‐2 regulates Src activation via repression of the CHK/MATK tumor suppressor in osteosarcoma

MMP‐2 regulates Src activation via repression of the CHK/MATK tumor suppressor in osteosarcoma

Comparison of the protective effects of curcumin and caffeic acid phenethyl ester against doxorubicin‐induced testicular toxicity

Sublethal doxorubicin promotes migration and invasion of breast cancer cells: role of Src Family non-receptor tyrosine kinases

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