American Association for Cancer Research
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Figure S6 from RAC1b Overexpression Confers Resistance to Chemotherapy Treatment in Colorectal Cancer

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posted on 2023-04-03, 16:11 authored by Erik T. Goka, Pallavi Chaturvedi, Dayrelis T. Mesa Lopez, Adriana De La Garza, Marc E. Lippman

Figure S6. (A) Five different colorectal cancer cells showing the sensitivity for GYS32661, KRAS and BRAF mutation and Rac1b expression. (B) HCT116-EV and HCT116-Rac1b cells stably expressing the NFκÎ' reporter was treated with different dose of GYS32661. The cells were lysed in reporter lysis buffer and NFκB reporter activity was measured. The results, presented as the NF-kB-mediated luciferase activity normalized to the protein concentration are the means {plus minus} SEM from three independent experiments. (C) Mice body weight following treatment with GYS32661.



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-κB signaling. Here, we show that Rac1b overexpression correlates with cancer stage and confirmed Rac1b expression is associated with increased growth through enhancing NF-κB activity. Rac1b knockdown reduced cellular proliferation and reduced NF-κB activity. Surprisingly, Rac1b expression and NF-κB activity were upregulated in cells treated with chemotherapeutics, suggesting that Rac1b facilitates chemo-resistance through activation of NF-κB 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-κB 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-κB signaling, providing a novel strategy to overcome resistance to chemotherapy in colorectal cancer.

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