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

Wu, Lawrence Shih Hsin; Zhang, Jiansheng; Wu, Huiguo; Han, En-Kun

doi:10.1016/j.bbrc.2015.09.068

Cited by 19 publications

(17 citation statements)

References 32 publications

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“…Nevertheless, enhanced repair of DDP-induced DNA damage can render tumor cells more resistant to DDP (Bradbury and Middleton, 2004). Given the important role of DNA-PKcs in DNA repair, various approaches including chemical inhibitor (Wu et al, 2015) and small interfering RNAs (Tang et al, 2014) targeting PRKDC/DNA-PKcs are developed. As a key component of DNA-PK, DNA-PKcs, which is encoded by PRKDC, plays a pivotal role in the non-homologous end joining (NHEJ) pathway by binding to DNA ends and recruiting a series of DNA repair enzymes (Davidson et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…As a key component of DNA-PK, DNA-PKcs, which is encoded by PRKDC, plays a pivotal role in the non-homologous end joining (NHEJ) pathway by binding to DNA ends and recruiting a series of DNA repair enzymes (Davidson et al, 2013). Given the important role of DNA-PKcs in DNA repair, various approaches including chemical inhibitor (Wu et al, 2015) and small interfering RNAs (Tang et al, 2014) targeting PRKDC/DNA-PKcs are developed. These experiments have shown encouraging results in improving drug resistance.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA‐488‐3p sensitizes malignant melanoma cells to cisplatin by targeting PRKDC

et al. 2017

Cell Biology International

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Deregulation of microRNAs (miRNAs) has been implicated in drug resistance in various types of cancers, including malignant melanoma (MM). MiR-488-3p has been reported as a tumor suppressor in several cancers. However, the exact expression patterns of miR-488-3p and the precise molecular mechanisms underlying its role in MM remain largely unknown and require further investigation. In this study, we demonstrated that miR-488-3p is significantly downregulated in MM clinical specimens and cell lines. Ectopic expression of miR-488-3p resulted in markedly increased drug sensitivity of MM cells in vitro and in vivo. The DNA-activated, catalytic polypeptide (PRKDC), which encodes DNA-dependent protein kinase catalytic subunit (DNA-PKcs), was identified as a direct target of miR-488-3p using luciferase reporter assays, qRT-PCR, and western blotting analyses. PRKDC knockdown by small interfering RNA (siRNA) alone promoted sensitivity of MM cells to cisplatin (DDP) while overexpression of PRKDC partially rescued the miR-488-3p-mediated acceleration of sensitivity to DDP in MM cells. Taken together, our results indicate that miR-488-3p serves as a drug resistance sensitizer in MM, supporting its potential as a promising therapeutic candidate.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MicroRNA‐488‐3p sensitizes malignant melanoma cells to cisplatin by targeting PRKDC

et al. 2017

Cell Biology International

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“…The results have proposed that DNA-PKcs could be an important oncogene which promotes cancer initiation, progression, and apoptosis-resistance [17, 19, 20, 31–35]. In many different cancers, DNA-PKcs is over-expressed and represents a novel and important oncotarget [17, 19, 20, 31–35]. …”

Section: Discussionmentioning

confidence: 99%

Identification of DNA-PKcs as a primary resistance factor of salinomycin in osteosarcoma cells

Zhen

Zhu

et al. 2016

Oncotarget

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Malignant osteosarcoma (OS) is still a deadly disease for many affected patients. The search for the novel anti-OS agent is extremely urgent and important. Our previous study has proposed that salinomycin is a novel anti-OS agent. Here we characterized DNA-dependent protein kinase catalytic subunit (DNA-PKcs) as a primary salinomycin resistance factor in OS cells. DNA-PKcs inhibitors (NU7026, NU7441 and LY294002) or DNA-PKcs shRNA knockdown dramatically potentiated salinomycin-induced death and apoptosis of OS cells (U2OS and MG-63 lines). Further, forced-expression of microRNA-101 (“miR-101”) downregulated DNA-PKcs and augmented salinomycin's cytotoxicity against OS cells. Reversely, over-expression of DNA-PKcs in OS cells inhibited salinomycin's lethality. For the mechanism study, we show that DNA-PKcs is required for salinomycin-induced pro-survival autophagy activation. DNA-PKcs inhibition (by NU7441), shRNA knockdown or miR-101 expression inhibited salinomycin-induced Beclin-1 expression and autophagy induction. Meanwhile, knockdown of Beclin-1 by shRNA significantly sensitized salinomycin-induced OS cell lethality. In vivo, salinomycin administration suppressed U2OS xenograft tumor growth in severe combined immuno-deficient (SCID) mice, and its anti-tumor activity was dramatically potentiated with co-administration of the DNA-PKcs inhibitor NU7026. Together, these results suggest that DNA-PKcs could be a primary resistance factor of salinomycin in OS cells. DNA-PKcs inhibition or silence may thus significantly increase salinomycin's sensitivity in OS cells.

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“…Interestingly, this suggested that targeting NHEJ and HR could be used as a new synthetic lethal approach in anti-cancer treatment [ 258 ]. Furthermore, it has been shown that NU7441 (and NU7026) could dramatically enhance WAY-600 (a potent mTOR inhibitor) cytotoxic and pro-apoptotic effect against colorectal cancer cells [ 259 ].…”

Section: The Non-homologous End-joining (Nhej) Proteinsmentioning

confidence: 99%

DNA Damage Signalling and Repair Inhibitors: The Long-Sought-After Achilles’ Heel of Cancer

et al. 2015

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For decades, radiotherapy and chemotherapy were the two only approaches exploiting DNA repair processes to fight against cancer. Nowadays, cancer therapeutics can be a major challenge when it comes to seeking personalized targeted medicine that is both effective and selective to the malignancy. Over the last decade, the discovery of new targeted therapies against DNA damage signalling and repair has offered the possibility of therapeutic improvements in oncology. In this review, we summarize the current knowledge of DNA damage signalling and repair inhibitors, their molecular and cellular effects, and future therapeutic use.

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

Cited by 19 publications

References 32 publications

MicroRNA‐488‐3p sensitizes malignant melanoma cells to cisplatin by targeting PRKDC

MicroRNA‐488‐3p sensitizes malignant melanoma cells to cisplatin by targeting PRKDC

Identification of DNA-PKcs as a primary resistance factor of salinomycin in osteosarcoma cells

DNA Damage Signalling and Repair Inhibitors: The Long-Sought-After Achilles’ Heel of Cancer

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