The Myc proto-oncogene family consists of three members,C-MYC,MYCN,and MYCL,which encodes the transcription factor c-Myc(hereafter Myc),N-Myc,and L-Myc,respectively.Myc protein orchestrates diverse physiological proce...The Myc proto-oncogene family consists of three members,C-MYC,MYCN,and MYCL,which encodes the transcription factor c-Myc(hereafter Myc),N-Myc,and L-Myc,respectively.Myc protein orchestrates diverse physiological processes,including cell proliferation,differentiation,survival,and apoptosis.Myc modulates about 15%of the global transcriptome,and its deregulation rewires the cellular signaling modules inside tumor cells,thereby acquiring selective advantages.The deregulation of Myc occurs in>70%of human cancers,and is related to poor prognosis;hence,hyperactivated Myc oncoprotein has been proposed as an ideal drug target for decades.Nevertheless,no specific drug is currently available to directly target Myc,mainly because of its"undruggable"properties:lack of enzymatic pocket for conventional small molecules to bind;inaccessibility for antibody due to the predominant nucleus localization of Myc.Although the topic of targeting Myc has actively been reviewed in the past decades,exciting new progresses in this field keep emerging.In this review,after a comprehensive summarization of valuable sources for potential druggable targets of Myc-driven cancer,we also peer into the promising future of utilizing macropinocytosis to deliver peptides like Omomyc or antibody agents to intracellular compartment for cancer treatment.展开更多
Although significant progress has been made in the development of novel targeted drugs for the treatment of acute myeloid leukemia(AML)in recent years,chemotherapy still remains the mainstay of treatment and the overa...Although significant progress has been made in the development of novel targeted drugs for the treatment of acute myeloid leukemia(AML)in recent years,chemotherapy still remains the mainstay of treatment and the overall survival is poor in most patients.Here,we demonstrated the antileukemia activity of a novel small molecular compound NL101,which is formed through the modification on bendamustine with a suberanilohydroxamic acid(SAHA)radical.NL101 suppresses the proliferation of myeloid malignancy cells and primary AML cells.It induces DNA damage and caspase 3-mediated apoptosis.A genome-wide clustered regularly interspaced short palindromic repeats(CRISPR)library screen revealed that phosphatase and tensin homologous(PTEN)gene is critical for the regulation of cell survival upon NL101 treatment.The knockout or inhibition of PTEN significantly reduced NL101-induced apoptosis in AML and myelodysplastic syndrome(MDS)cells,accompanied by the activation of protein kinase B(AKT)signaling pathway.The inhibition of mammalian target of rapamycin(mTOR)by rapamycin enhanced the sensitivity of AML cells to NL101-induced cell death.These findings uncover PTEN protein expression as a major determinant of chemosensitivity to NL101 and provide a novel strategy to treat AML with the combination of NL101 and rapamycin.展开更多
基金This work is supported by National Cancer Institute 2R01CA139158Lymphoma SPORE Career Enhancement and Development Research Program Grants(W.H.)+2 种基金National Natural Science Foundation of China 31970555(Y.G.)Fundamental Research Funds for the Central Universities 2020FZZX001-09National Natural Science Foundation of China 32070630(J.Z.).
文摘The Myc proto-oncogene family consists of three members,C-MYC,MYCN,and MYCL,which encodes the transcription factor c-Myc(hereafter Myc),N-Myc,and L-Myc,respectively.Myc protein orchestrates diverse physiological processes,including cell proliferation,differentiation,survival,and apoptosis.Myc modulates about 15%of the global transcriptome,and its deregulation rewires the cellular signaling modules inside tumor cells,thereby acquiring selective advantages.The deregulation of Myc occurs in>70%of human cancers,and is related to poor prognosis;hence,hyperactivated Myc oncoprotein has been proposed as an ideal drug target for decades.Nevertheless,no specific drug is currently available to directly target Myc,mainly because of its"undruggable"properties:lack of enzymatic pocket for conventional small molecules to bind;inaccessibility for antibody due to the predominant nucleus localization of Myc.Although the topic of targeting Myc has actively been reviewed in the past decades,exciting new progresses in this field keep emerging.In this review,after a comprehensive summarization of valuable sources for potential druggable targets of Myc-driven cancer,we also peer into the promising future of utilizing macropinocytosis to deliver peptides like Omomyc or antibody agents to intracellular compartment for cancer treatment.
基金supported by the Zhejiang Provincial Natural Science Foundation of China(No.LY21H080005)the National Natural Science Foundation of China(Nos.81572920 and 82100171).
文摘Although significant progress has been made in the development of novel targeted drugs for the treatment of acute myeloid leukemia(AML)in recent years,chemotherapy still remains the mainstay of treatment and the overall survival is poor in most patients.Here,we demonstrated the antileukemia activity of a novel small molecular compound NL101,which is formed through the modification on bendamustine with a suberanilohydroxamic acid(SAHA)radical.NL101 suppresses the proliferation of myeloid malignancy cells and primary AML cells.It induces DNA damage and caspase 3-mediated apoptosis.A genome-wide clustered regularly interspaced short palindromic repeats(CRISPR)library screen revealed that phosphatase and tensin homologous(PTEN)gene is critical for the regulation of cell survival upon NL101 treatment.The knockout or inhibition of PTEN significantly reduced NL101-induced apoptosis in AML and myelodysplastic syndrome(MDS)cells,accompanied by the activation of protein kinase B(AKT)signaling pathway.The inhibition of mammalian target of rapamycin(mTOR)by rapamycin enhanced the sensitivity of AML cells to NL101-induced cell death.These findings uncover PTEN protein expression as a major determinant of chemosensitivity to NL101 and provide a novel strategy to treat AML with the combination of NL101 and rapamycin.
