RAC1 GTPase promotes the survival of breast cancer cells in response to hyper-fractionated radiation treatment

Hein, Ashley L.; Post, Carl M.; Sheinin, Yuri; Lakshmanan, Imayavaramban; Natarajan, Amarnath; Enke, Charles Arthur; Batra, Surinder K.; Ouellette, Michel; Yan, Ying

doi:10.1038/onc.2016.163

Cited by 63 publications

(53 citation statements)

References 61 publications

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“…Similar results were shown in doxorubicin-resistant squamous cell carcinoma (SCC), were pharmacological inhibition of Rac1 restores doxorubicin sensitivity (48). Rac1 expression is also implicated in radioresistance in different cancer cell types such as breast cancer, glioblastoma, pancreatic, and cervical cancers (49,50,51,52).…”

Section: Discussionsupporting

confidence: 57%

RAC1b Overexpression Confers Resistance to Chemotherapy Treatment in Colorectal Cancer

Goka¹,

Chaturvedi²,

Lopez³

et al. 2019

Molecular Cancer Therapeutics

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Resistance to chemotherapy represents a major limitation in the treatment of colorectal cancer. Novel strategies to circumvent resistance are critical to prolonging patient survival. Rac1b, a constitutively activated isoform of the small GTPase Rac1, is upregulated with disease progression and promotes cell proliferation and inhibits apoptosis by activation of NF-kB signaling. Here, we show that Rac1b overexpression correlates with cancer stage and confirmed Rac1b expression is associated with increased growth through enhancing NF-kB activity. Rac1b knockdown reduced cellular proliferation and reduced NF-kB activity. Surprisingly, Rac1b expression and NF-kB activity were upregulated in cells treated with chemotherapeutics, suggesting that Rac1b facilitates chemo-resistance through activation of NF-kB signaling. Knockdown of Rac1b or Rac inhibition increases the sensitivity of the cells to oxaliplatin. When used in combination, inhibition of Rac prevents the increase in NF-kB activity associated with chemotherapy treatment and increases the sensitivity of the cells to oxaliplatin. Although Rac inhibition or oxaliplatin treatment alone reduces the growth of colorectal cancer in vivo, combination therapy results in improved outcomes compared with single agents alone. We provide the first evidence that Rac1b expression confers resistance to chemotherapy in colorectal cancer. Additionally, we show that the use of a Rac inhibitor prevents chemoresistance by blocking activation of chemotherapy induced NF-kB signaling, providing a novel strategy to overcome resistance to chemotherapy in colorectal cancer.

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Section: Discussionsupporting

confidence: 57%

RAC1b Overexpression Confers Resistance to Chemotherapy Treatment in Colorectal Cancer

Goka¹,

Chaturvedi²,

Lopez³

et al. 2019

Molecular Cancer Therapeutics

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“…Rac1 expression is elevated in breast cancer cells that survive radiation treatment, and survival is mediated by the Erk and NF-κB pathways. There have been numerous examples of sensitization of cancer cells to ionizing radiation by Rac inhibition, such as the reported effect of NSC23766 and dominant-negative Rac1 in breast cancer cells (64). The fact that all forms of resistance described above can be reverted by inhibition of Rac1 highlight the potential use of the pharmacological inhibition of this GTPase to overcome resistance in the clinic.…”

Section: Targeting Rac Gtpases: Can We Overcome Therapy Resistance?mentioning

confidence: 99%

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

2017

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Rho family GTPases are critical regulators of cellular functions that play important roles in cancer progression. Aberrant activity of Rho small G-proteins, particularly Rac1 and their regulators, is a hallmark of cancer, and contributes to the tumorigenic and metastatic phenotypes of cancer cells. This review examines the multiple mechanisms leading to Rac1 hyperactivation, particularly focusing on emerging paradigms that involve gain-of-function mutations in Rac and guanine nucleotide exchange factors (GEFs), defects in Rac1 degradation, and mislocalization of Rac signaling components. The unexpected pro-oncogenic functions of Rac GTPase activating proteins (GAPs) also challenged the dogma that these negative Rac regulators solely act as tumor suppressors. The potential contribution of Rac hyperactivation to resistance to anti-cancer agents, including targeted therapies, as well as to the suppression of anti-tumor immune response, highlights the critical need to develop therapeutic strategies to target the Rac pathway in a clinical setting.

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“…Radiation therapy is a common treatment method for cancer, whereas radioresistance of cancer cells is a huge clinical problem . Tumor radioresistance is a major reason for decreased efficiency of cancer radiation therapy .…”

Section: Discussionmentioning

confidence: 99%

Activation of PTGS2/NF‐κB signaling pathway enhances radiation resistance of glioma

Tan

Liu

et al. 2019

Cancer Medicine

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Objective We focused on the effects of PTGS2/NF‐κB signaling pathway on the radiation resistance of glioma in the study. Methods We downloaded the microarray data from the Gene Expression Omnibus (GEO) database. We verified transfection successfully through QRT‐PCR analysis. Immunofluorescence was used to detect γH2AX content under 2 Gy radiation. The survival rates of cells under 2 Gy irradiation were tested by clonogenic survival assay. Flow cytometry was used to detect cell cycle. Western blot was applied to detect the expression of NF‐κB pathway‐related proteins. We also used MTT assay to detect the proliferation of cells. Results In this research, we discovered that the expression of the PTGS2 was upregulated in radiation‐resistant glioma cells. The radio‐tolerance rate of U87 cells was obviously elevated after the overexpression of PTGS2. The radioresistance of U87R cells was significantly reduced after the knockdown of PTGS2. After radiotherapy, the number of cells arrested in G2/M phase decreased after PTGS2 overexpression in U87cells but increased in PTGS2 knockdown in U87R cells. The survival rate of U87 and U87R cells under radiation decreased significantly after the addition of NF‐κB inhibitor. The proliferation of U87 cells was suppressed by radiation and the addition of Bay 11. In addition, PTGS2 activated NF‐κB signaling pathway and prevented DNA damage after radiotherapy. Lastly, PTGS2 was proved to facilitate tumor cell proliferation and improve the radio‐tolerance. Conclusion PTGS2/NF‐κB signaling pathway was involved in radio‐tolerance of glioma cells, which provided a new insight into glioma therapy.

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RAC1 GTPase promotes the survival of breast cancer cells in response to hyper-fractionated radiation treatment

Cited by 63 publications

References 61 publications

RAC1b Overexpression Confers Resistance to Chemotherapy Treatment in Colorectal Cancer

RAC1b Overexpression Confers Resistance to Chemotherapy Treatment in Colorectal Cancer

The Rac GTPase in Cancer: From Old Concepts to New Paradigms

Activation of PTGS2/NF‐κB signaling pathway enhances radiation resistance of glioma

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