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Inhibition of AKT-Signaling Sensitizes Soft Tissue Sarcomas (STS) and Gastrointestinal Stromal Tumors (GIST) to Doxorubicin via Targeting of Homology-Mediated DNA Repair.

ABSTRACT: Activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is well documented for a broad spectrum of human malignancies supporting their growth and progression. Accumulating evidence has also implicated AKT as a potent modulator of anti-cancer therapies via regulation of DNA damage response and repair (DDR) induced by certain chemotherapeutic agents and ionizing radiation (IR). In the present study, we examined the role of AKT signaling in regulating of Rad51 turnover and cytotoxic effects of topoisomerase II inhibitor, doxorubicin (Dox) in soft tissue sarcomas (STS) and gastrointestinal stromal tumors (GIST) in vitro. Blocking of AKT signaling (MK-2206) enhanced cytotoxic and pro-apoptotic effects of Dox in vast majority of STS and GIST cell lines. The phosphorylated form of Akt co-immunoprecipitates with Rad51 after Dox-induced DNA damage, whereas Akt inhibition interrupts this interaction and decreases Rad51 protein level by enhancing protein instability via proteasome-dependent degradation. Inhibition of Akt signaling in Dox-treated cells was associated with the increased number of ?-H2AX-positive cells, decrease of Rad51 foci formation and its colocalization with ?-H2AX foci, thereby revealing unsuccessful DDR events. This was also in consistency with an increase of tail moment (TM) and olive tail moment (OTM) in Dox-treated GIST and STS cells cultured in presence of Akt inhibitor after Dox washout. Altogether, our data illustrates that inhibition of AKT signaling is STS and GIST might potentiate the cytotoxic effect of topoisomerase II inhibitors via attenuating the homology-mediated DNA repair.

SUBMITTER: Boichuk S

PROVIDER: S-EPMC7700672 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Inhibition of AKT-Signaling Sensitizes Soft Tissue Sarcomas (STS) and Gastrointestinal Stromal Tumors (GIST) to Doxorubicin via Targeting of Homology-Mediated DNA Repair.

Boichuk Sergei S Bikinieva Firuza F Nurgatina Ilmira I Dunaev Pavel P Valeeva Elena E Aukhadieva Aida A Sabirov Alexey A Galembikova Aigul A

International journal of molecular sciences 20201122 22

Activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is well documented for a broad spectrum of human malignancies supporting their growth and progression. Accumulating evidence has also implicated AKT as a potent modulator of anti-cancer therapies via regulation of DNA damage response and repair (DDR) induced by certain chemotherapeutic agents and ionizing radiation (IR). In the present study, we examined the role of AKT signaling in regulating of Rad51 turnover and cytotoxic eff ...[more]

PMID: 33266502

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Project description:Dysregulation of the fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) signaling pathway is frequently observed in multiple human malignancies, and thus, therapeutic strategies targeting FGFs and FGFRs in human cancer are being extensively explored. We observed the activation of the FGF/FGFR-signaling pathway in imatinib (IM)-resistant gastrointestinal stromal tumor (GIST) cells. Furthermore, we found that the activation of FGFR signaling has a significant impact on IM resistance in GISTs in vitro. Next, we tested the efficacy of BGJ398, a potent and selective FGFR1?3 inhibitor, in xenograft models of GISTs exhibiting secondary IM resistance due to receptor-tyrosine kinase (RTK) switch (loss of c-KIT/gain of FGFR2a). Five to eight-week-old female nu/nu mice were subcutaneously inoculated into the flank areas with GIST T-1R cells. Mice were randomized as control (untreated), IM, BGJ398, or a combination and treated orally for 12 days. IM had a moderate effect on tumor size, thus revealing GIST resistance to IM. Similarly, a minor regression in tumor size was observed in BGJ398-treated mice. Strikingly, a 90% decrease in tumor size was observed in mice treated with a combination of IM and BGJ398. Treatment with BGJ398 and IM also induced major histopathologic changes according to a previously defined histopathologic response score and resulted in massive myxoid degeneration. This was associated with increased intratumoral apoptosis as detected by immunohistochemical staining for cleaved caspase-3 on day 5 of the treatment. Furthermore, treatment with BGJ398 and IM significantly reduced the proliferative activity of tumor cells as measured by positivity for Ki-67 staining. In conclusion, inhibition of FGFR signaling substantially inhibited the growth of IM-resistant GISTs in vitro and showed potent antitumor activity in an IM-resistant GIST model via the inhibition of proliferation, tumor growth, and the induction of apoptosis, thereby suggesting that patients with advanced and metastatic GISTs exhibiting IM resistance might benefit from therapeutic inhibition of FGFR signaling.

Dataset Information

Inhibition of AKT-Signaling Sensitizes Soft Tissue Sarcomas (STS) and Gastrointestinal Stromal Tumors (GIST) to Doxorubicin via Targeting of Homology-Mediated DNA Repair.

Publications

Inhibition of AKT-Signaling Sensitizes Soft Tissue Sarcomas (STS) and Gastrointestinal Stromal Tumors (GIST) to Doxorubicin via Targeting of Homology-Mediated DNA Repair.

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