title: DAB2IP regulates autophagy in prostate cancer in response to combined treatment of radiation and a DNA-PKcs inhibitor.
abstract: Radiation therapy (RT) is an effective strategy for the treatment of localized prostate cancer (PCa) as well as local invasion. However, some locally advanced cancers develop radiation resistance and recur after therapy; therefore, the development of radiation-sensitizing compounds is essential for treatment of these tumors. DOC-2/DAB2 interactive protein (DAB2IP), which is a novel member of the Ras-GTPase activating protein family and a regulator of phosphatidylinositol 3-kinase-Akt activity, is often downregulated in aggressive PCa. Our previous studies have shown that loss of DAB2IP results in radioresistance in PCa cells primarily because of accelerated DNA double-strand break (DSB) repair kinetics, robust G(2)/M checkpoint control, and evasion of apoptosis. A novel DNA-PKcs inhibitor NU7441 can significantly enhance the effect of radiation in DAB2IP-deficient PCa cells. This enhanced radiation sensitivity after NU7441 treatment is primarily due to delayed DNA DSB repair. More significantly, we found that DAB2IP-deficient PCa cells show dramatic induction of autophagy after treatment with radiation and NU7441. However, restoring DAB2IP expression in PCa cells resulted in decreased autophagy-associated proteins, such as LC3B and Beclin 1, as well as decreased phosphorylation of S6K and mammalian target of rapamycin (mTOR). Furthermore, the presence of DAB2IP in PCa cells can lead to more apoptosis in response to combined treatment of NU7441 and ionizing radiation. Taken together, NU7441 is a potent radiosensitizer in aggressive PCa cells and DAB2IP plays a critical role in enhancing PCa cell death after combined treatment with NU7441 and radiation.
authors: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9187, USA.
authors: Lan
authors: L
authors: Yu
authors: Vasu
authors: V
authors: Tumati
authors: Shu-Fen
authors: SF
authors: Tseng
authors: Feng-Ming
authors: FM
authors: Hsu
authors: D Nathan
authors: DN
authors: Kim
authors: David
authors: D
authors: Hong
authors: Jer-Tsong
authors: JT
authors: Hsieh
authors: Corbin
authors: C
authors: Jacobs
authors: Payal
authors: P
authors: Kapur
authors: Debabrata
authors: D
authors: Saha
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000532:radiotherapy; D017209:Apoptosis; D001343:Autophagy; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000187:drug effects* / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000378:metabolism*; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors; D018572:Disease-Free Survival; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000532:radiotherapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034741:RNA, Small Interfering; D011836:Radiation Tolerance / Q000187:drug effects*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C499693:8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one; D002867:Chromones; C462952:DAB2IP protein, human; D004273:DNA, Neoplasm; D009025:Morpholines; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D020703:ras GTPase-Activating Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D058570:TOR Serine-Threonine Kinases