title: mTOR inhibition sensitizes ONC201-induced anti-colorectal cancer cell activity.
abstract: We here tested the anti-colorectal cancer (CRC) activity by a first-in-class small molecule TRAIL inducer ONC201. The potential effect of mTOR on ONC201's actions was also examined. ONC201 induced moderate cytotoxicity against CRC cell lines (HT-29, HCT-116 and DLD-1) and primary human CRC cells. Significantly, AZD-8055, a mTOR kinase inhibitor, sensitized ONC201-induced cytotoxicity in CRC cells. Meanwhile, ONC201-induced TRAIL/death receptor-5 (DR-5) expression, caspase-8 activation and CRC cell apoptosis were also potentiated with AZD-8055 co-treatment. Reversely, TRAIL sequestering antibody RIK-2 or the caspase-8 specific inhibitor z-IETD-fmk attenuated AZD-8055 plus ONC201-induced CRC cell death. Further, mTOR kinase-dead mutation (Asp-2338-Ala) or shRNA knockdown significantly sensitized ONC201's activity in CRC cells, leading to profound cell death and apoptosis. On the other hand, expression of a constitutively-active S6K1 (T389E) attenuated ONC201-induced CRC cell apoptosis. For the mechanism study, we showed that ONC201 blocked Akt, but only slightly inhibited mTOR in CRC cells. Co-treatment with AZD-8055 also concurrently blocked mTOR activation. These results suggest that mTOR could be a primary resistance factor of ONC201 in CRC cells.
authors: Department of Colorectal Surgery, Hangzhou Red Cross Hospital, Hangzhou, China.
authors: Zhe-Zhu
authors: ZZ
authors: Jin
authors: Department of Colorectal Surgery, Hangzhou Red Cross Hospital, Hangzhou, China.
authors: Wei
authors: W
authors: Wang
authors: Department of Colorectal Surgery, Hangzhou Red Cross Hospital, Hangzhou, China.
authors: Di-Long
authors: DL
authors: Fang
authors: Department of Colorectal Surgery, Hangzhou Red Cross Hospital, Hangzhou, China. Electronic address: jin_yongjun82@126.com.
authors: Yong-Jun
authors: YJ
authors: Jin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles; D009025:Morpholines / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D007093:Imidazoles; D009025:Morpholines; D011725:Pyridines; D011743:Pyrimidines; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C585684:TIC10 compound; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: AZD-8055; Colorectal cancer; ONC201; TRAIL; mTOR