Abstract

BackgroundIncreased reactive oxygen species (ROS) production by arsenic treatment in solid tumors showed to be effective to sensitize cancer cells to chemotherapies. Arsenic nano compounds are known to increase the ROS production in solid tumors.MethodsIn this study we developed arsenic–ferrosoferric oxide conjugated Nano Complex (As2S2–Fe3O4, AFCNC) to further promote the ROS induction ability of arsenic reagent in solid tumors. We screen for the molecular pathways that are affect by arsenic treatment in ESCC cancer cells. And explored the underlying molecular mechanism for the arsenic mediated degradations of the key transcription factor we identified in the gene microarray screen. Mouse xenograft model were used to further verify the synthetic effects of AFCNC with chemo and radiation therapies, and the molecular target of arsenic treatment is verified with IHC analysis.ResultsWith gene expression microarray analysis we found Hippo signaling pathway is specifically affected by arsenic treatment, and induced ubiquitination mediated degradation of YAP in KYSE-450 esophageal squamous cell carcinoma (ESCC) cells. Mechanistically we proved PML physically interacted with YAP, and arsenic induced degradation PML mediated the degradation of YAP in ESCC cells. As a cancer stem cell related transcription factor, YAP 5SA over expressions in cancer cells are correlated with resistance to chemo and radiation therapies. We found AFCNC treatment inhibited the increased invasion and migration ability of YAP 5SA overexpressing KYSE-450 cells. AFCNC treatment also effectively reversed protective effects of YAP 5SA overexpression against cisplatin induced apoptosis in KYSE-450 cells. Lastly, with ESCC mouse xenograft model we found AFCNC combined with cisplatin treatment or radiation therapy significantly reduced the tumor volumes in vivo in the xenograft ESCC tumors.ConclusionsTogether, these findings suggested besides ROS, YAP is a potential target for arsenic based therapy in ESCC, which should play an important role in the synthetic effects of arsenic nano complex with chemo and radiation therapy.

Highlights

  • Increased reactive oxygen species (ROS) production by arsenic treatment in solid tumors showed to be effective to sensitize cancer cells to chemotherapies

  • We found combined administration of arsenic–ferrosoferric oxide conjugated nano complex (AFCNC) with cisplatin or radiation therapy significantly inhibited tumor growth rates in the human Esophageal squamous cell carcinoma (ESCC) mice xenograft model compared with cisplatin or radiation treatment alone

  • Our findings suggested arsenic–ferrosoferric oxide conjugated Nano Complex could be used in combination with chemo or radiation therapy to target the cancer stem cell population of ESCC to inhibit treatments induced tumor dormancy and relapse [16]

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Summary

Introduction

Increased reactive oxygen species (ROS) production by arsenic treatment in solid tumors showed to be effective to sensitize cancer cells to chemotherapies. Arsenic nano compounds are known to increase the ROS production in solid tumors. Wang et al reported arsenic trioxide inhibited transcriptional activity of SRF/ MCM7 in liver cancer stem cells to inhibit metastasis of hepatocellular carcinoma [7]. Diepart et al reported by inhibiting mitochondria respiration of the cancer cells, single dose of arsenic trioxide treatment induced upregulation of oxygenation and increased the sensitivity to radiation therapy of solid tumors [8]. In this study we developed arsenic–ferrosoferric oxide ­(As2S2–Fe3O4) conjugated Nano Complex (AFCNC) to increase the ROS production efficacy of arsenic sulfide nano particle by promoting Fenton reactions [11]

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