Inhibition of RAC1 GTPase sensitizes pancreatic cancer cells to γ-irradiation

Abstract

Radiation therapy is a staple treatment for pancreatic cancer. However, owing to the intrinsic radioresistance of pancreatic cancer cells, radiation therapy often fails to increase survival of pancreatic cancer patients. Radiation impedes cancer cells by inducing DNA damage, which can activate cell cycle checkpoints. Normal cells possess both a G1 and G2 checkpoint. However, cancer cells are often defective in G1 checkpoint due to mutations/alterations in key regulators of this checkpoint. Accordingly, our results show that normal pancreatic ductal cells respond to ionizing radiation (IR) with activation of both checkpoints whereas pancreatic cancer cells respond to IR with G2/M arrest only. Overexpression/hyperactivation of Rac1 GTPase is detected in the majority of pancreatic cancers. Rac1 plays important roles in survival and Ras-mediated transformation. Here, we show that Rac1 also plays a critical role in the response of pancreatic cancer cells to IR. Inhibition of Rac1 using specific inhibitor and dominant negative Rac1 mutant not only abrogates IR-induced G2 checkpoint activation, but also increases radiosensitivity of pancreatic cancer cells through induction of apoptosis. These results implicate Rac1 signaling in the survival of pancreatic cancer cells following IR, raising the possibility that this pathway contributes to the intrinsic radioresistance of pancreatic cancer.

Retracted: MicroRNA‑224 promotes the sensitivity of osteosarcoma cells to cisplatin by targeting Rac1

“…Rac1 overexpression has been found in various types of cancer, such as lung cancer, gastric cancer, pancreatic cancer, bladder cancer and breast cancer 43, 44, 45, 46, 47. Moreover, activation of Rac1 can increase cancer cell migration, adhesion, invasion, proliferation and metastasis 40, 44, 48, 49, 50.…”

MAGE-A9 in head and neck cancer: Prognostic value and preclinical findings in the context of irradiation

“…Additionally, the co-occurrence of alterations in MAGE-A9 and Rac1 is highly significantly associated with poorer overall survival (median survival in the altered group: 35.45 months; in the unaltered group: 67.81 months; P=0.00299) in HNSCC (42,43). Rac1 is a known factor contributing to chemoresistance and radioresistance, particularly in HNSCC (44)(45)(46).…”

Rac1 is a potential target to circumvent radioresistance

“…As illustrated in Figure 1, Yan and colleagues, reported RAC1 (Ras-related C3 botulinum toxin substrate 1) as a potential target to reduce radioresistance in breast cancer cells (7) as well as pancreatic cancer cells (8). Rac1, a member of Rho family GTPase, functions as a binary molecular switch by cycling between an inactive GDP-bound and an active GTP-bound state.…”

“…Rac1 GTPase is overexpressed or hyperactivated in various types of tumors and implicates in tumorigenesis, angiogenesis, invasion and metastasis (9). It has been repeatedly reported that Rac1 can be activated by IR treatment in some types of tumor cells, including breast cancer (10), pancreatic cancer (8), and head and neck squamous cell carcinoma (7) and is involved in the formation of radioresistance. In 2012, Yan and colleagues reported that IR induced G2/M checkpoint arrest through activation of ATM/ATR pathway and inhibition of Cdc25 phosphatase in breast cancers, but accompanied with the activation of ERK1/2 signaling, suggesting a potential survival signal contributing the development of radioresistance.…”

“…In addition to activating pro-survival pathways, Rac1 is also involved in cell invasion and metastasis of breast cancer by regulating actin cytoskeletal structure (11). IR has been reported to process a pro-metastatic transeffect, which rests on the endothelial radiation response promoting the extravasation of circulating tumor cells, in a RAC1-dependent manner (12 (7), pancreatic (8), and head and neck squamous cell carcinoma (HNSCC) (13). Both RAC1 and phosphatidylinositol 3,4,5-trisphosphate-dependent Rac guanine nucleotide exchange factor-1 (P-Rex1), highly overexpressed in breast cancers, can be activated by GPCR CXCR4 or ErbB signaling pathways to contribute to breast cancer cells progression and proliferation and their insensitization to antiestrogen therapy (14,15).…”