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.

Sensitization of radio-resistant prostate cancer cells with a unique cytolethal distending toxin

“…Furthermore, a single-nucleotide polymorphism probe (rs1571801) in the DAB2IP gene has been nominally associated with aggressive PCa phenotypes [30-33]. In addition, the DAB2IP expression level determined by immunohistochemical staining of needle biopsy specimens from PCa patients has been shown to be associated with recurrence-free survival in a retrospective cohort analysis [34]. These findings suggest that DAB2IP is a prognostic marker for aggressive PCa.…”

Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

“…56 Interestingly, DAB2IP-depleted cells have increased mTOR-S6K pathway activation and significantly more autophagy, suggesting that in normal cells DAB2IP inhibits autophagy, and loss of such inhibition in cancer contributes to radiation resistance. 57 DAB2IP loss in prostate cancer cells was also shown to enhance chemoresistance by upregulation of the antiapoptotic protein clusterin. 58 Similarly, by augmenting STAT3 activation and survivin expression, loss of DAB2IP facilitates survival of prostate cancer cells after androgen deprivation therapy.…”

DOC-2/DAB2 Interacting Protein Status in High-Risk Prostate Cancer Correlates With Outcome for Patients Treated With Radiation Therapy

“…14, 21 Furthermore, cells which lack DAB2IP are more likely to undergo autophagy, rather than apoptosis, in response to ionizing radiation. 15 Based on strong preclinical data indicating the role of DAB2IP in radiation response in prostate cancer cells, we sought to determine its clinical impact 15 . However, the tumor environment is a complex milieu with multiple interacting activators and inhibitors.…”

“…While several cell culture and animal based models have shown that DAB2IP and EZH2 are involved with increased radiation resistance, 14, 15, 21 there is no study that evaluates the clinical relevance of DAB2IP-mediated radiation resistance. Therefore, we sought to determine the prognostic value of DAB2IP and its upstream regulator EZH2 in high-risk prostate cancer patients.…”