Study On The Mechanism Of Hedgehog Signaling Pathway In The Regulation Of Tumor Resistance And Its Targeted Drug Resistance Reversal Agent

Acquired chemotherapeutic resistance is one of the most important challanges in tumor chemotherapy. Hence, understanding of its mechanism is of great significance, as it may improve the efficiency of tumor chemotherapy and promote the prognosis of tumor patients. Abundant studies have shown that various mechanisms might be responsible for acquired chemotherapeutic resistance, including aberrant expression of ATP-binding cassette (ABC) transporters, changes of metabolic transformation and drug targets, defects related to apoptosis and enhancement of the capacity to repair damaged DNA. Recently reports have linked the tumor initiating cells to acquired chemoresistance.The hedgehog (Hh) signaling system conserved in organisms ranging from insects to mammals plays a crucial role in embryonic development, as well as post-embryonic tissue homeostasis through influences on stem or progenitor cells. With further development, it is discovered that Hh also has a close relationship with the occurrence of acquired chemotherapeutic resistance. Additionally, accumulating findings have linked Hh pathway to acquired chemo-resistance through transcriptionally controlling the expression of ABC transporters. However, it remains unclear whether and how Hh pathway may maintain the chemo-resistance phenotype through controlling the tumor initiating cells properties of acquired chemoresistant cancer cells.In this study, using well established acquired chemoresistant cell lines and chemosensitive cancer cells K562and KB, we provide a series of complimentary evidences to show that Hh promotes non-ABC dependent chemoresistance by maintaining the tumor-initiating cells properties of chemoresistant cells via direct transcriptionally controlling the expression of transcriptional factors twistl and snail. Meanwhile, our observation that twistl, like snail does, represents a direct transcriptional target of Hh pathway increases the depth of our knowledge about the association between Hh pathway and twistl. Additionally, our present study reveals that twistl in combination with snail bridges a link between Hh and tumor initiating cells properties and consequently chemoresistance independent of ABC transporters, thus exposing a novel and promising strategy for circumventing acquired chemoresistance. Hence, our present study together with other reports demonstrates that Hh may promote acquired chemoresistance via two independent mechanisms:/). transcriptionally controlling the expression of ABC transporters such as MDR1and BCRP;ii). endowing cancer cells with tumor-initiating cells properties by transcriptionally controlling the expression of twistl and snail.In view of the significance role of Hh pathway in acquired chemotherapeutic resistance, it might be an ideal strategy for reversing chemotherapeutic resistance by targeting Hh signaling pathway. Therefore, we make an attempt to establish an evaluation model of Hh signaling pathway, in finding the reversal agents through inhibiting Hh signaling pathway. After screening a series of compounds using Hh pathway transcription factor Gli luciferase reporter assay, we find ligands, including EVn-50and VB1, have a remarkable inhibition of Hh signaling pathway, suggesting that they are potential acquired chemotherapeutic resistance reversal agents targeting Hh pathway.Hence, our study further elucidate the mechanism on Hh signaling pathway, and lay a theoretical foundation for reversing acquired chemotherapeutic resistance through Hh pathway. Meanwhile, we present here that twistl, like snail, is also a direct transcriptional target of Hh signaling pathway, thus improving our knowledge of molecular basics underpinning the regulation of EMT and consequently metastasis of cancers mediated by Hh. In addition, there is vital significance on finding new type reversal agents with independent intellectual property rights.