The Rold Testicular Orphan Receptor4(TR4)in Radiotherapy For Prostate Cancer

Background and objective:Prostate cancer (PCa) is one of the most common malignant tumors in male genitourinary system, and has surpassed lung cancer as the most prevalent cancer among males in United States, and is the second leading cause of cancer death in American men. Radiotherapy is one of the principle treatment options for clinical localized PCa. However, a significant number of PCa may show different resistance to radiotherapy, and tumor may recur fast after treatment. The mechanisms of such differential radio-resistance, however, remain unclear. Overcoming this radio-resistance is clinically important and became important research focus.A major determinant of tumor response to ionizing radiation is tumor cell’s radio-sensitivity, which dependent on its capability of repairing DNA damage. Based on understanding of radiation biology, there are different DNA repair mechanisms between tumor and normal cells. Therefore, reducing the capacity of DNA damage repair could sensitize tumor cells to radiotherapy.Testicular orphan nuclear receptor4(TR4) is a member of the nuclear receptor superfamily. It has been investigated that TR4could function through its various down-stream target genes to influence the intracellular ROS and oxidative stress resistance, and DNA damage resistance. However, the relationship between TR4and PCa’s radio-sensitivity remains unclear.In this study, we examined the TR4expression in PCa samples from patients receiving brachytherapy and investigated its potential linkage to the biochemical recurrence (BCR) after radiotherapy. We also modulated the TR4expression in PCa cells to study its influence on PCa cell’s radio-sensitivity via in vitro experiments.Methods and results:1. TR4expression might influence the outcome of radiotherapy in PCa patients.To study the potential role of TR4on the radio-sensitivity of PCa, we first compare the TR4expression in13biopsy samples from PCa patients who had BCR after brachytherapy to another13biopsy samples from PCa patients without BCR. Immunohistochemistry (IHC) results showed that TR4expression is much higher in biopsy samples from BCR PCa patients as compared to those from non-recurrent PCa patients (69.23%vs15.38%, Fisher’s exact test, p=0.02), suggesting that higher TR4expression in PCa tissue might relate to the higher rate of BCR after radiotherapy.2. Targeting TR4gene alters prostate cancer cell’s radio-sensitivity.We applied in vitro cell lines to examine the TR4influence on cell’s radio-sensitivity. We first alter the TR4expression in PCa cells by two different approaches:overexpressed and knocking-down. We then compared these PCa cell’s radio-sensitivity after treated with ionizing radiation. Results suggest that alternation of TR4in PCa cells might also influence the cell viability and survival rate to radiotherapy and targeting TR4might lead to increase radio-sensitivity to kill PCa cells. And TR4might function through modulation of DNA damage-repair pathway to alter the radio-sensitivity in PCa cells.Conclusion:In summary, modulating the TR4expression level in PCa could influences their radio-sensitivity. Higher TR4expression in PCa may increase the resistance of radiotherapy for PCa. TR4might become a new potential biomarker for predicting the prognosis of radiotherapy for PCa patients. Combinational therapy with radiotherapy plus a new target to suppress TR4may become a new potential therapy with better efficacy to battle PCa in future.