High levels of X-linked Inhibitor-of-Apoptosis Protein (XIAP) are indicative of radio chemotherapy resistance in rectal cancer

Abstract

BackgroundThe mainstay of treatment in rectal cancer is neoadjuvant radio chemotherapy prior to surgery, in an attempt to downstage the tumour, allowing for more complete removal during surgery. In 40 % of cases however, this neoadjuvant radio chemotherapy fails to achieve tumour regression, partly due insufficient apoptosis signaling. X-linked Inhibitor of Apoptosis Protein (XIAP) is an anti-apoptotic protein that has been reported to contribute to disease progression and chemotherapy resistance.MethodsWe obtained rectal biopsy normal and matched tumour tissue from 29 rectal cancer patients with varying degrees of tumour regression, and using Western blot, examined anti-apoptotic XIAP and pro-apoptotic Smac protein levels in these tissues, with the aim to examine whether disturbed XIAP/Smac levels may be an indicator of neoadjuvant radio chemotherapy resistance. Expression of inhibitor of apoptosis proteins cIAP-1 and cIAP-2 was also examined.ResultsWe found that levels of XIAP increased in accordance with the degree of radio chemotherapy resistance of the tissue. Levels of this protein were also significantly higher in tumour tissue, compared to matched normal tissue in highly resistant tissue. In contrast, Smac protein levels did not increase with radio chemotherapy resistance, and the protein was similarly expressed in normal and tumour tissue, indicating a shift in the balance of these proteins. Post treatment surgical resection tissue was available for 8 patients. When we compared matched tissue pre- and post- radio chemotherapy we found that XIAP levels increased significantly during treatment in both normal and tumour tissue, while Smac levels did not change. cIAP-1 and cIAP-2 levels were not differentially expressed in varying degrees of radio chemotherapy resistance, and neoadjuvant therapy did not alter expression of these proteins.ConclusionThese data indicate that disturbance of the XIAP/Smac balance may be a driver of radio chemotherapy resistance, and hence high levels of XIAP may be a useful indicator of neoadjuvant radio chemotherapy resistance in rectal cancer. Moreover, as XIAP levels increase with radio chemotherapy it is possible that a subset of more resistant tumour cells survive this treatment and may be resistant to further adjuvant treatment. Patients with resistant tumours highly expressing XIAP may benefit from alternative treatment strategies, such as Smac mimetics post neoadjuvant radio chemotherapy.

CHK1 Inhibition Radiosensitizes Head and Neck Cancers to Paclitaxel-Based Chemoradiotherapy

“…High expression of these proteins has previously been linked to radiation resistance and worse prognosis (29)(30)(31)(32). During this study, it was noted that despite HN5 cells being highly radioresistant they were more sensitive to CCT244747 monotherapy, as well as CCT244747 combined therapies, than HN4 cells.…”

Role of the tumor microenvironment in regulating apoptosis and cancer progression

“…However, Smac levels did not increase with the radio-chemotherapy resistance, and it was similarly expressed in tumor and normal tissues. This disturbance of XIAP/Smac balance may strongly contribute to tumor cells survival and therapies resistance 23 . One of the mechanisms by which tumors resist to apoptosis is the upregulation of the antiapoptotic protein "c-FLIP" (cellular FLICE inhibitory protein) which blocks apoptosis mediated by death receptors, such as Fas, DR4 (TRAIL-R1) and DR5 (TRAIL-R2).…”

Radiation induced transcriptional and post-transcriptional regulation of the hsa-miR-23a ~ 27a ~ 24-2 cluster suppresses apoptosis by stabilizing XIAP

“…All three miRNAs displayed a regulatory effect on XIAP expression suggesting a synergistic action on this gene. XIAP is an attractive prognostic marker and therapeutic target in cancer treatment, since it undergoes unique interactions with terminal effector caspases and can act as block for apoptosis [42][43][44][45]. It has been shown to be often deregulated in different cancers, which can also affect cancer treatment [46][47][48].…”