Abstract
The senescence-associated secretory phenotype (SASP) can be provoked by side effects of therapeutic agents, fueling advanced complications including cancer resistance. However, the intracellular signal network supporting initiation and development of the SASP driven by treatment-induced damage remains unclear. Here we report that the transcription factor Zscan4 is elevated for expression by an ATM-TRAF6-TAK1 axis during the acute DNA damage response and enables a long term SASP in human stromal cells. Further, TAK1 activates p38 and PI3K/Akt/mTOR to support the persistent SASP signaling. As TAK1 is implicated in dual feedforward mechanisms to orchestrate the SASP development, pharmacologically targeting TAK1 deprives cancer cells of resistance acquired from treatment-damaged stromal cells in vitro and substantially promotes tumour regression in vivo. Together, our study reveals a novel network that links functionally critical molecules associated with the SASP development in therapeutic settings, thus opening new avenues to improve clinical outcomes and advance precision medicine.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Carcinoma, Ductal / drug therapy
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Carcinoma, Ductal / genetics
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Carcinoma, Ductal / metabolism
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Carcinoma, Ductal / pathology
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line
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Cellular Senescence / drug effects
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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Everolimus / pharmacology
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Female
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Gene Expression Regulation, Neoplastic*
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Humans
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Lactones / pharmacology
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology
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MAP Kinase Kinase Kinases / antagonists & inhibitors
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MAP Kinase Kinase Kinases / genetics*
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MAP Kinase Kinase Kinases / metabolism
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Male
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Mammary Glands, Human / drug effects
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Mammary Glands, Human / metabolism
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Mammary Glands, Human / pathology
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Mice
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Mice, SCID
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Mitoxantrone / pharmacology
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Phenotype
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Prostate / drug effects
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Prostate / metabolism
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Prostate / pathology
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Resorcinols / pharmacology
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Signal Transduction
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Stromal Cells / drug effects
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Stromal Cells / metabolism
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Stromal Cells / pathology
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Xenograft Model Antitumor Assays
Substances
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7-oxozeanol
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Antineoplastic Agents
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DNA-Binding Proteins
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Lactones
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Resorcinols
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Transcription Factors
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ZSCAN4 protein, human
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Everolimus
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Mitoxantrone
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7