Focal adhesion kinase Fakir et al also known as non

Focal adhesion kinase (Fakir et al., 2006), also known as non-receptor tyrosine kinase (PTK2), is a 125-kDa protein that regulates cell migration, adhesion, proliferation, and survival (Tavora et al., 2014; Yang et al., 2016; Tian et al., 2017). Many studies have observed FAK overexpression and/or hyper-phosphorylation in a variety of human tumors (Chikara et al., 2017). In lung cancer, high FAK activity is involved in radioresistance (Beinke et al., 2003). In head and neck cancer, inhibiting FAK can increase the efficacy of RT (Hehlgans et al., 2009). Previous studies have found that the damage endured by the intestinal and rectal tissue under irradiation mainly involves intestinal epithelial prostaglandin synthase (Yan et al., 2012). However, the molecular mechanism underlying radiation-induced intestinal and rectal injury remains unknown. In this study, we found that FAK was related to rectal injury, and further investigated the mechanism of FAK in radiation-induced rectal injury.
Materials and methods
Results
Discussion Radiation-induced damage to normal tissues is a common side effect of radiotherapy in cancer patients. Acute radiation proctitis happens at the time of or shortly after IR to the pelvic area and includes several symptoms such as rectal bleeding, rectal pain, diarrhea, urgency, frequency, and loose stool. This condition seriously damages patients' quality of life, although most acute radiation proctitis is self-limited. In addition, patients may not be able to tolerate radiotherapy, and may quit treatment, which affects treatment outcomes (Theis et al., 2010). The pathophysiology of radiation proctitis includes DNA damage or intestinal epithelial cell death, resulting in mucosal barrier disruption and an inflammatory response (Hauer-Jensen et al., 2014). To decrease injury to normal tissues, the radiation sensitivity of a patient should be predicted before radiotherapy. FAK activity is mediated by the integrin signaling pathway (Burridge et al., 1988; Leng et al., 2016). The phosphorylation site of FAK is Tyr (Tyr397), which is a crucial indicator of cell adhesion (Thanapprapasr et al., 2017). FAK is overexpressed in many human cancers (Zhao and Guan, 2009; Hehlgans et al., 2012). Studies in head and neck cancer indicated that FAK plays an important role in the response of cells to ionizing radiation (Eke et al., 2012). In head and neck squamous cell carcinoma, FAK was identified as a crucial determinant of radiation survival via AKT1 and ERK1/2 signaling (Hehlgans et al., 2012). In breast cancer, HER2 can decrease radiosensitivity by activating FAK, and the radiosensitivity in HER2-overexpressing cells was restored upon FAK inhibition using a FAK inhibitor (Hou et al., 2016). FAK can inhibit p53 expression (Papp et al., 2001), and WT p53 protein has been demonstrated to promote radiation-induced apoptosis (Liu et al., 2007). P53 plays a critical role in regulating cell apoptosis in many tumors by repairing damaged DNA. P53 can activate the process of apoptosis to sweep away the damaged cells when DNA repair fails (Cui et al., 2018). The tumor suppressor p53 can trigger apoptosis via activating the bax (Follis et al., 2015). Previous reports have indicated that FAK expression induces radioresistance (Luo et al., 2014; Hou et al., 2016; Skinner et al., 2016). However, the involvement of FAK in HIEC cells remains unexplored. In this study, our data showed the role of FAK in mediating the radioresistance of HIEC cells. FAK knockdown obviously increased the radiosensitivity of HIEC cells, and mice treated with FAK inhibitors exhibited aggravated mice rectal damage. FAK binds PI3K via the Y397 autophosphorylation site. FAK phosphorylation and PI3K activation can activate AKT kinase. Then, AKT can inhibit apoptosis via regulating a variety of cell death-related proteins. The PI3K/AKT signaling pathway plays a crucial part in various cellular functions (Hay, 2005). It is also well-known that PI3K/AKT is an anti-radiation survival pathway for cells (Lin et al., 2012; Qiu et al., 2012), and many studies have found that AKT is also a radiation-related gene (Kunnimalaiyaan et al., 2006; Liou et al., 2009). In pancreatic cancer, inhibiting the activity of the PI3K/AKT pathway can attenuate DNA repair by efficiently inhibiting ATM and DNA-PKcs, two major kinases related to radiation-induced DNA DSBs, leading to sustained DNA damage (Liu et al., 2015; Park et al., 2017). The previous studies have found that FAK activates the downstream PI3K/AKT signaling pathway in HIEC cells (Leng et al., 2016), and treatment with FAK siRNA or FAK inhibitor significantly increased the expression of γH2AX protein in HIEC cells induced by radiation in this study (Fig. 2E and F).