RAC1b Overexpression Confers Resistance to Chemotherapy Treatment in Colorectal Cancer

Abstract

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.

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

“…Numerous studies have implicated Rac/PAK activities with the maintenance of mesenchymal stem cell-like populations in epithelial cancers; and thus, therapy resistance (Zhao et al, 2011;Ong et al, 2013;Zhu et al, 2015;Goel et al, 2016;Huynh et al, 2016;Aboukameel et al, 2017;Lai et al, 2017;Morrison Joly et al, 2017;Cardama et al, 2018;Goka et al, 2019). Specifically in breast cancer, Rac/Cdc42/PAK signaling is implicated with therapy resistance of HER2-type (Wang et al, 2006;Ebi et al, 2013;Laurin et al, 2013;Dokmanovic et al, 2014;Desai et al, 2016;Hampsch et al, 2017), triple negative (De et al, 2017), and ER(+) cancers (Cai et al, 2003;Gonzalez et al, 2017).…”

RAC1 Involves in the Radioresistance by Mediating Epithelial-Mesenchymal Transition in Lung Cancer

“…When the PI3K/AKT pathway was activated, the expression and biological activity of Rac1 were significantly up-regulated (36). Meanwhile, RAC1b expression is positively associated with increased growth and chemo-resistance via enhancing NF-κB activity and then activating NF-κB signaling in colorectal cancer (45). In this report, we provide evidence that RAC1 promoted cell proliferation and colony formation in lung cancer cells; silencing of RAC1 expression inhibited pro-survival signal of lung cancer in vivo and in vitro.…”

Active RAC1 Promotes Tumorigenic Phenotypes and Therapy Resistance in Solid Tumors

“…Another contribution of RAC1 to the oncogenic transformation of cancer cells occurs through the RAC1b splice variant. The constitutively active, GTP-bound variant of RAC1, RAC1b, is preferentially expressed in both colon and breast cancers, enhancing the downstream activation of NF-κB and the induction of cyclin D1 expression in a variety of solid tumors [ 24 ]. Recently, Goka et al described RAC1b overexpression in colorectal cancer and its role in resistance to tumor progression and resistance to current standard-of-care chemotherapy regimens for the treatment of advanced colorectal cancers.…”

“…In response to oxaliplatin and 5-FU, colorectal cancer cells can overexpress RAC1b, which activates downstream NF-κB expression, thereby promoting cell survival gene transcription. During the validation of their hypothesis, the authors observed that RAC1b-knockdown mice were sensitized to oxaliplatin and 5-FU treatment [ 24 ]. Interestingly, however, RAC1b alone is insufficient to promote tumor initiation in the lung.…”

“…To achieve this function in solid tumors, RAC1 upregulates mitogenic growth factor signaling, stress response signaling, and the regulation of cell cycle checkpoints. Pro-proliferative effects are realized through a variety of stress-related cell-signaling proteins, splice variants [ 6 , 19 , 24 ], and the mitogenic/oncogenic PI3K and MAPK cell signaling pathways [ 14 , 26 , 27 ]. The pro-proliferative function of activated RAC1 by virtue of which it contributes to cancer progression and therapy resistance involves stress response proteins, including NF-κB, JNK, and p38.…”