1. Academic Validation
  2. DNA-PKcs interference sensitizes colorectal cancer cells to a mTOR kinase inhibitor WAY-600

DNA-PKcs interference sensitizes colorectal cancer cells to a mTOR kinase inhibitor WAY-600

  • Biochem Biophys Res Commun. 2015 Oct 23;466(3):547-53. doi: 10.1016/j.bbrc.2015.09.068.
Ling Wu 1 Jiansheng Zhang 1 Huiguo Wu 1 Enkun Han 2
Affiliations

Affiliations

  • 1 Gastrointestinal Surgery, Tianjin Baodi Hospital, Tianjin, 301800, China.
  • 2 Gastrointestinal Surgery, Tianjin Baodi Hospital, Tianjin, 301800, China. Electronic address: drhanenjun8@sina.com.
Abstract

Colorectal Cancer (CRC) is one leading contributor of cancer-related mortalities. Mammalian target of rapamycin (mTOR), existing in two complexes (mTORC1/2), is a valuable target for possible CRC interference. In the current study, we showed that WAY-600, a potent mTOR Inhibitor, only exerted moderate activity against primary and HT-29 CRC cells. We proposed that DNA-dependent protein kinase catalytic subunit (DNA-PKcs) could be the major resistance factor of WAY-600 in CRC cells. DNA-PKcs inhibitors, including NU7026 and NU7441, dramatically enhanced WAY-600-induced cytotoxic and pro-apoptotic effect against the CRC cells. Further, WAY-600-exerted cytotoxicity was significantly increased in DNA-PKcs-silenced (by targeted siRNA/shRNA) CRC cells, but was attenuated with DNA-PKcs overexpression. Our evidence suggested that DNA-PKcs Thr-2609 phosphorylation might be critical for WAY-600's resistance. Mutation of this site through introducing a dominant negative DNA-PKcs (T2609A) dramatically potentiated WAY-600's sensitivity in HT-29 cells. Meanwhile, overexpression of protein Phosphatase 5 (PP5) dephosphorylated DNA-PKcs at Thr-2609, and significantly increased WAY-600's sensitivity in HT-29 cells. In vivo, WAY-600-induced anti-HT-29 xenograft growth activity was significantly potentiated with NU7026 co-administration. These results suggest that DNA-PKcs could be the major resistance factor of WAY-600 in CRC cells.

Keywords

Chemo-sensitization; Colorectal cancer; DNA-PKcs; WAY-600; mTOR.

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