Abstract
BackgroundRadiation exerts direct antitumor effects and is widely used in clinics, but the efficacy is severely compromised by tumor resistance. Therefore uncovering the mechanism of radioresistance might promote the development of new strategies to overcome radioresistance by manipulating activity of the key molecules.MethodsImmunohistochemistry were used to find whether mTOR were over-activated in radioresistant patients’ biopsies. Then Western blot, real-time PCR and transfection were used to find whether radiotherapy regulates the expression and activity of mTOR by modulating its targeting microRNA in human pancreatic cancer cell lines PANC-1, Capan-2 and BxPC-3. Finally efficacy of radiation combined with mTOR dual inhibitor AZD8055 was assessed in vitro and in vivo.ResultsIonizing radiation promoted mTOR expression and activation in pancreatic cancer cells through reducing miR-99b expression, which negatively regulated mTOR. Novel mTOR inhibitor, AZD8055 (10 nM, 100 nM, 500 nM) synergistically promoted radiation (0–10 Gy) induced cell growth inhibition and apoptosis. In human pancreatic cancer xenografts, fractionated radiation combined with AZD8055 treatment further increased the anti-tumor effect, the tumor volume was shrinked to 278 mm3 after combination treatment for 3 weeks compared with single radiation (678 mm3) or AZD8055 (708 mm3) treatment (P < 0.01).ConclusionsOur data provide a rationale for overcoming radio-resistance by combined with mTOR inhibitor AZD8055 in pancreatic cancer therapy.
Highlights
Radiation exerts direct antitumor effects and is widely used in clinics, but the efficacy is severely compromised by tumor resistance
Results mammalian target of rapamycin (mTOR) was upregulated in pancreatic cancer patients subjected to radiotherapy some signaling cascades such as Ras/PI3K/ PTEN/Akt/mTOR, Ras/Raf/MEK/ERK and p53 have been implicated in regulation of tumor radioresistance, the detail mechanism is still largely unknown
Western blot further confirmed that the level of active phosphorylated S6 (p-S6) as the key downstream molecule of mTOR signaling pathway was consistently up-regulated in the samples upon stimulation with radiation (Figure 1B)
Summary
Radiation exerts direct antitumor effects and is widely used in clinics, but the efficacy is severely compromised by tumor resistance. 10-15% patients undergo surgery due to late diagnosis, radiotherapy becomes the major way in the treatment of pancreatic cancers in clinics, either alone or in combination with chemotherapy [1]. Local control of tumor growth is partly achieved by radiation-induced cell death as a result of damage to cell membranes and DNA [2,3]. Accumulating evidence demonstrated that mTOR was dysregulated in various cancers, its over-expression and over-activation contribute to cancer progression and drug-resistance [7,8]. MTOR inhibitors represent a promising therapeutic approach for cancer and solid tumors [9,10]
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