ANXA2 could act as a moderator of EGFR-directed therapy resistance in triple negative breast cancer

Zhang, Yue; Bi, Jiajia; Zhu, Hongtao; Shi, Mei; Zeng, Xianlu

doi:10.1080/09168451.2018.1484275

Cited by 12 publications

(6 citation statements)

References 34 publications

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“…Several studies have shown that chemotherapeutic agents can enhance phosphorylation of Anxa2 in cancer cells [12,27], and anti-cancer drugs have been shown to induce highly aggressive phenotypes in resistant cells [9,11,58]. Additionally, phosphorylated Anxa2 confers resistance in several cancer cells [45,59]. Consistent with other studies, we have proven that Anxa2 Tyr23 phosphorylation is critical in the invasion and metastasis of many types of cancer [48,56,60].…”

Section: Discussionsupporting

confidence: 90%

Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells

Fan

et al. 2019

Breast Cancer Res

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Background: Acquirement of resistance is always associated with a highly aggressive phenotype of tumor cells. Recent studies have revealed that Annexin A2 (Anxa2) is a key protein that links drug resistance and cancer metastasis. A high level of Anxa2 in cancer tissues is correlated to a highly aggressive phenotype. Increased Anxa2 expression appears to be specific in many drug-resistant cancer cells. The functional activity of Anxa2 is regulated by tyrosine phosphorylation at the Tyr23 site. Nevertheless, the accurate molecular mechanisms underlying the regulation of Anxa2 tyrosine phosphorylation and whether phosphorylation is necessary for the enhanced invasive phenotype of drug-resistant cells remain unknown. Methods: Small interfering RNAs, small molecule inhibitors, overexpression, loss of function or gain of function, rescue experiments, Western blot, wound healing assays, transwell assays, and in vivo metastasis mice models were used to investigate the functional effects of Rack1 and Src on the tyrosine phosphorylation of Anxa2 and the invasion and metastatic potential of drug-resistant breast cancer cells. The interaction among Rack1, Src, and Anxa2 in drug-resistant cells was verified by co-immunoprecipitation assay. Results: We demonstrated that Anxa2 Tyr23 phosphorylation is necessary for multidrug-resistant breast cancer invasion and metastasis. Rack1 is required for the invasive and metastatic potential of drug-resistant breast cancer cells through modulating Anxa2 phosphorylation. We provided evidence that Rack1 acts as a signal hub and mediates the interaction between Src and Anxa2, thereby facilitating Anxa2 phosphorylation by Src kinase. Conclusions: Our findings suggest a convergence point role of Rack1/Src/Anxa2 complex in the crosstalk between drug resistance and cancer aggressiveness. The interaction between Anxa2 and Rack1/Src is responsible for the association between drug resistance and invasive/metastatic potential in breast cancer cells. Thus, our findings provide novel insights on the mechanism underlying the functional linkage between drug resistance and cancer aggressiveness.

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Section: Discussionsupporting

confidence: 90%

Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells

Fan

et al. 2019

Breast Cancer Res

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“…AnxA2 likely controls actin-membrane dynamics to enable lateral EGFR movements at the cell surface and/or EGFR internalization and sorting in early endosomes [22,23,26]. Elevated AnxA2 levels correlate with poor survival and may moderate resistance to EGFR-directed therapy in triple negative breast cancer [59,60]. In addition, AnxA2 together with EGFR, is reciprocally regulated to ErbB2 in Herceptin-resistant breast cancers [61] and seems to contribute to the acquired resistance of non-small cell lung cancers to EGFR-TKIs [62].…”

Section: Discussionmentioning

confidence: 99%

Annexin A6 improves anti‐migratory and anti‐invasive properties of tyrosine kinase inhibitors in EGFR overexpressing human squamous epithelial cells

et al. 2020

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Annexin A6 (AnxA6), a member of the calcium (Ca 2+ ) and membrane binding annexins, is known to stabilize and establish the formation of multifactorial signaling complexes. At the plasma membrane, AnxA6 is a scaffold for protein kinase Cα (PKCα) and GTPase activating protein p120GAP to promote downregulation of epidermal growth factor receptor (EGFR) and Ras/mitogen activated protein kinase (MAPK) signaling. In human squamous A431 epithelial carcinoma cells, which overexpress EGFR, but lack endogenous AnxA6, restoration of AnxA6 expression (A431-A6) promotes PKCα-mediated threonine 654 (T654)-EGFR phosphorylation, which inhibits EGFR tyrosine kinase activity. This is associated with reduced A431-A6 cell growth, but also decreased migration and invasion in wound healing, matrigel and organotypic matrices. Here we show that A431-A6 cells display reduced EGFR activity in vivo, with xenograft analysis identifying increased pT654-EGFR levels, but reduced tyrosine EGFR phosphorylation compared to controls. In contrast, PKCα depletion in A431-A6 tumors is associated with strongly reduced pT654 EGFR levels, yet increased EGFR tyrosine phosphorylation and MAPK activity. Moreover, tyrosine kinase inhibitors (TKIs; gefitinib, erlotinib) more effectively inhibit cell viability, clonogenic growth, and wound healing of A431-A6 cells compared to controls. Likewise, the ability of AnxA6 to inhibit A431 motility and invasiveness strongly improve TKI efficacy in matrigel invasion assays. This correlates with a greatly reduced invasion of the surrounding matrix of TKI-treated A431-A6 when cultured in 3D-spheroids. Altogether these findings implicate that elevated AnxA6 scaffold levels contribute to improve TKI-mediated inhibition of growth and migration, but also invasive properties in EGFR overexpressing human squamous epithelial carcinoma.

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“…Mycoplasma membrane protein P37 can interact with Anxa2 of the HCC cells and induce mycoplasma-associated multidrug resistance of HCC 138 , and as mentioned above, Anxa2 mediates the cisplatin resistance in NSCLC via regulating p53 pathway 36 . Anxa2 also regulates NF-κB signaling as a study showed two ginsenosides inhibit the interaction between Anxa2 and NF-κB then increase the apoptosis in cancer cells 139 , and it is remarkably upregulated in chemo-resistant neuroblastoma cell lines and induces drug resistance through NF-κB activation and nuclear translocation 42 . EGFR expression is elevated in TNBC, but TNBC patients cannot benefit from EGFR-targeted therapy.…”

Section: Effect Of Anxa2 In Cancer Treatment Resistance and Prospect ...mentioning

confidence: 99%

Crucial role of Anxa2 in cancer progression: highlights on its novel regulatory mechanism

Wang

Niu

et al. 2019

Cancer Biol Med

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Anxa2 is the most studied member of the calcium-mediated phospholipid-binding protein family annexins and is a biomarker in cancers. In this review, we listed clinical findings and confirmed the value of Anxa2 in early diagnosis and prognostic prediction due to its overexpression and adverse effect on the outcome in most tumors. Anxa2 plays a pivotal role in cancer cell proliferation, migration, invasion, metastasis, and treatment resistance. Improved understanding of its cancer-promoting function might make it an ideal target for cancer therapy. Here, we systematically summarized the mechanism of Anxa2 in regulating epithelial-mesenchymal transition (EMT), cytoskeleton dynamicity, cell cycle, apoptosis, angiogenesis, and immunology by using various tumor models. These data emphasize the potential of Anxa2 for targeted intervention in tumors. Altering Anxa2 expression, neutralizing the cell surface Anxa2, or inhibiting its activation, such as through Tyr23 phosphorylation, could be considered based on the regulatory mechanism of Anxa2 in tumor progression.

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ANXA2 could act as a moderator of EGFR-directed therapy resistance in triple negative breast cancer

Cited by 12 publications

References 34 publications

Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells

Rack1 mediates tyrosine phosphorylation of Anxa2 by Src and promotes invasion and metastasis in drug-resistant breast cancer cells

Annexin A6 improves anti‐migratory and anti‐invasive properties of tyrosine kinase inhibitors in EGFR overexpressing human squamous epithelial cells

Crucial role of Anxa2 in cancer progression: highlights on its novel regulatory mechanism

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