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NVP-BEZ235 inhibits thyroid cancer growth by p53- dependent/independent p21 upregulation.

ABSTRACT: NVP-BEZ235 is a novel dual PI3K/mTOR inhibitor, currently in phase 1/2 clinical trials, exhibiting clinical efficiency in treatment of numerous malignancies including thyroid cancer. Cancer cells harboring mutant p53 was widely reported to be blunt to pharmaceutical therapies. However, whether this genotype dependent effect also presents in thyroid cancer when treated with NVP-BEZ235 remains unknown. Therefore, in this study, the tumor suppressing effects of NVP-BEZ235 in thyroid cancer cell lines and in-vivo xenograft mouse model harboring different p53 status were examined. The antitumor effects were confirmed in p53 mutant thyroid cancer cells, though less prominent than p53 wild type cells. And for the p53 mutant cells, p53-independent upregulation of p21 plays a critical role in their response to NVP-BEZ235. Moreover, GSK3β/β-catenin signaling inhibition was implicated in the p21-mediated G₀/G₁ cell cycle arrest in both p53 wild type and mutant thyroid cancer cells treated with NVP-BEZ235.

SUBMITTER: Ruan B

PROVIDER: S-EPMC6990918 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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NVP-BEZ235 inhibits thyroid cancer growth by p53- dependent/independent p21 upregulation.

Ruan Banjun B Liu Wei W Chen Pu P Cui Rongrong R Li Yu Y Ji Meiju M Hou Peng P Yang Qi Q

International journal of biological sciences 20200114 4

NVP-BEZ235 is a novel dual PI3K/mTOR inhibitor, currently in phase 1/2 clinical trials, exhibiting clinical efficiency in treatment of numerous malignancies including thyroid cancer. Cancer cells harboring mutant p53 was widely reported to be blunt to pharmaceutical therapies. However, whether this genotype dependent effect also presents in thyroid cancer when treated with NVP-BEZ235 remains unknown. Therefore, in this study, the tumor suppressing effects of NVP-BEZ235 in thyroid cancer cell lin ...[more]

PMID: 32025215

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Project description:In spite of the promising in vitro and preclinical results, dual PI3K/Akt/mTOR inhibitor NVP-BEZ235, and ATP-competitive mTOR inhibitor PP242 both failed to confirm their inhibitory efficacy against renal cell carcinoma (RCC) in clinical settings. Therefore, a better understanding of the molecular mechanism is essential so as to provide possibilities for their use in combination with other agents. In present study, RCC cell lines (UMRC6, 786-0 and UOK121) were treated with NVP-BEZ235, PP242 or Rapamycin, an mTOR complex 1 (mTORC1)-specific inhibitor. They all suppressed cell proliferation and invasion, induced apoptosis and cell cycle arrest, and the effects were in the order of NVP-BEZ235 > PP242 > Rapamycin. Accordingly, the marked and sustained decrease in speckle-type POZ protein (SPOP) expression and phosphorylation of Akt and mTOR kinases was observed in RCC cells treated with NVP-BEZ235 and PP242, whereas only potent inhibition of mTOR activity was induced in Rapamycin-treated cells. In considering the overactivation of c-Jun and IκB-α in human renal tumor tissue, we next investigated the role of JNK and IKK pathways in the response of RCC cells to these compounds. First of all, transforming growth factor β activated kinase 1 (TAK1)-dependent activation of JNK/ (activator protein-1) AP-1 axis in RCC cells was proved by the repression of AP-1 activity with TAK1 or JNK inhibitor. Second, the profound inhibition of TAK1/JNK/AP-1 pathway was demonstrated in RCC cells treated with NVP-BEZ235 or PP242 but not Rapamycin, which is manifested as a reduction in activity of TAK1, c-Jun and AP-1. Meanwhile, subsequent to TAK1 inactivation, the activation of IκB-α was also reduced by NVP-BEZ235 and PP242. Likewise, in vivo, treatment with NVP-BEZ235 and PP242 suppressed the growth of xenografts generated from 786-0 and A498 cells, along with decreased expression of phospho-TAK1, phospho-c-Jun, and phospho-IκB-α. In contrast, Rapamycin elicited no significant inhibitory effects on tumor growth and phosphorylation of TAK1, c-Jun and IκB-α. We conclude that besides PI3K/Akt/mTOR signaling, NVP-BEZ235, and PP242 simultaneously target TAK1-dependent pathways in RCC cells. Notably, these effects were more marked in the presence of NVP-BEZ235 than PP242, indicating the potential application of NVP-BEZ235 in combination therapy for RCC.

Project description:BackgroundCancer treatment using gold (I) complexes is becoming popular. In this study, a gold (I) N-heterocyclic complex designated as complex 3 was synthesized, its cytotoxicity was examined, and its anti-melanoma activity was evaluated in vitro and in vivo.MethodsViability of cancer cells was determined by MTT assay upon treatment with various concentrations of a gold (I) N-heterocyclic carbene complex (complex 3) in a dose and time dependent manner. Mouse melanoma cells B16F10 were selected for further apoptotic studies, including flowcytometric analysis of annexin binding, cell cycle arrest, intracellular ROS generation and loss in the mitochondrial membrane potential. ELISA based assays were done for caspase activities and western blots for determining the expression of various survival and apoptotic proteins. Immunocytology was performed to visualize the translocation of p53 to the nucleus. B16F10 cells were inoculated into mice and post tumor formation, complex 3 was administered. Immunohistology was performed to determine the expressions of p53, p21, NF-κB (p65 and p50), MMP-9 and VEGF. Student's t test was used for determining statistical significance. The survival rate data were analyzed by Kaplan-Meier plots.ResultsComplex 3 markedly inhibited the growth of HCT 116, HepG2, and A549, and induced apoptosis in B16F10 cells with nuclear condensation, DNA fragmentation, externalization of phosphatidylserine, activation of caspase 3 and caspase 9, PARP cleavage, downregulation of Bcl-2, upregulation of Bax, cytosolic cytochrome c elevation, ROS generation, and mitochondrial membrane potential loss indicating the involvement of an intrinsic mitochondrial death pathway. Further, upregulation of p53, p-p53 (ser 15) and p21 indicated the role of p53 in complex 3 mediated apoptosis. The complex reduced tumor size, and caused upregulation of p53 and p21 along with downregulation of NF-κB (p65 and p50), VEGF and MMP-9. These results suggest that it induced anti-melanoma effect in vitro and in vivo by modulating p53 and other apoptotic factors.ConclusionsThe gold (I) N-heterocyclic carbene complex (C22H26N6AuO2PF6) designated as complex 3 induced ROS and p53 dependent apoptosis in B16F10 cells involving the mitochondrial death pathway along with suppression of melanoma tumor growth by regulating the levels of pro and anti apoptotic factors (p53, p21, NF-κB, VEGF and MMP-9).

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NVP-BEZ235 inhibits thyroid cancer growth by p53- dependent/independent p21 upregulation.

Publications

NVP-BEZ235 inhibits thyroid cancer growth by p53- dependent/independent p21 upregulation.

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