Abstract 1797: Downregulation of ribosomal protein S6 overcomes radioresistance in prostate cancer

Radiation Therapy (RT) is a definitive treatment for early-localized prostate cancer (PCA), but is associated with side effects which impair quality of life in addition to development of radioresistance. PI3K/Akt/mTOR signaling is one of the contributors to therapeutic resistance, including radioresistance. Ribosomal protein S6 (rpS6), a downstream effector of PI3K/Akt/mTOR signaling, mediates radioresistance by increasing protein synthesis, cell survival and epithelial mesenchymal transition. Also, increased activation of rpS6 is correlated with poor survival in PCA. Therefore, downregulation of rpS6 could decrease RT induced toxic side effects by sensitizing tumor cells. Based on published evidence demonstrating tumor growth inhibitory activities, we tested if Nexrutine® (Nx), an inexpensive OTC herbal supplement from Phellodendron amurense bark extract, could potentiate RT by inhibiting rpS6 activation. Using clonogenic assays, low dose RT in combination with Nx was found to have similar inhibition of surviving fraction compared to high dose RT in androgen independent PC-3 cells. Isobologram analysis of these data depicted strong synergism. In addition, increased activation of Akt/NFKB signaling molecules was observed in PC-3 cells exposed to radiation. The observed radiation-induced increase in these signaling molecules was either abolished (p-rpS6, p-NFKB and p-p70S6K) or decreased (p-Akt) in cells pretreated with Nx (8 hours) prior to RT. Additionally, Nx pretreatment prolonged the G2/M arrest caused by RT in PC-3 cells. Strikingly, knockdown of rpS6 in PC-3 cells reversed the observed effects of Nx, indicating the importance of rpS6 in mediating these changes. Furthermore, administration of Nx in combination with RT inhibited prostate tumor progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with no prominent toxicity. Notably, immunohistochemical analysis revealed decreased levels of p-mTOR, p70S6K, NFKB, Ki67 and Cyclin D1 in the prostate in combination group of animals compared to monotherapy. Taken together, our data suggest that Nx sensitizes PCA cells by down regulating rpS6 and delays progression to lethal disease. Remarkably, in a recent phase 0/1 study patients (81%) receiving Nx showed decreased PSA levels with no signs of grade 3 toxicity. Thus, Nx shows immense potential for use as an adjuvant in combination with conventional therapy for effective clinical management of PCA. Supported by NCCAM (R01 AT-007448) and VA-MERIT Award (I01 BX 000766; APK) Citation Format: Suleman S. Hussain, Paul Rivas, Roble G. Bedolla, Nikos Papanikolaou, Robert L. Reddick, Brad H. Pollock, Daniel C. Chan, Rita Ghosh, Addanki P. Kumar. Downregulation of ribosomal protein S6 overcomes radioresistance in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1797. doi:10.1158/1538-7445.AM2015-1797