Age is a major risk factor in the development of cancer(1). In addition to the accumulation of epithelial cell mutations, the age-dependent accumulation of senescent stromal cells plays an important role in tumor promotion(1-5). Although senescent cells no longer replicate, they remain metabolically active and secrete a wide variety of protumorigenic factors known as the senescence-associated secretory phenotype(2,6-8) (SASP). Through the SASP, senescent cells promote the transformation of preneoplastic cells in vitro and promote tumor growth in xenograft models(2,6-8). Osteopontin (OPN) is a protumorigenic protein that is upregulated at the mRNA level in response to senescence. Importantly, senescent cells depleted of OPN lack the tumor-promoting ability of normal senescent fibroblasts. Furthermore, the addition of recombinant OPN to preneoplastic epithelial cells is sufficient to induce cell proliferation. Understanding how SASP factors are regulated is an important step in designing stroma-targeted cancer therapies. The regulation of many SASP factors is well studied and dependent on ATM and NF-?B. However, the induction of OPN is independent of both of these factors. To study the regulation of OPN in response to senescence, we used OPN promoter reporter constructs to identify regions of the promoter required for robust activation of OPN transcription during senescence. We found that a region 190 base pairs upstream of the transcription start site housed critical sequences required for activation of OPN in response to senescence. This senescence response element (OPN-SRE) contains c-Myb and C/EBP? transcription factor binding sites, suggesting that these factors are important for the activation of OPN transcription in response to senescence. I hypothesize that c-Myb and C/EBP? cooperate to directly activate OPN transcription in response to senescence. To test this hypothesis, this proposal will pursue three aims: 1) determine c-Myb's role in OPN expression during senescence;2) determine C/EBP?'s role in OPN expression in during senescence 3) determine whether c-Myb and C/EBP? coordinately activate OPN in response to senescence. In addressing these aims, I will elucidate an independent SASP regulatory arm and the mechanism of transcriptional regulation of OPN. Further, I will determine whether C/EBP? acts as an essential central regulator of SASP, providing insight into the mechanism of SASP activation as a whole. Because senescent cells promote every stage of the tumorigenic process through the SASP, understanding these regulatory pathways will provide potential cancer therapeutic opportunities.
Senescent cells promote tumorigenesis through the senescence-associated secretory phenotype (SASP). However, depleting cells of OPN abrogates their protumorigenic capabilities. The mechanism that regulates OPN expression in senescent cells is independent of other SASP factors but remains unknown. Understanding the mechanism of OPN regulation in response to senescence may lead to novel therapeutic approaches for cancer as well as enhance the understanding of SASP regulation thus revealing additional therapeutic targets.
|Murali, Bhavna; Ren, Qihao; Luo, Xianmin et al. (2018) Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss. Cancer Res 78:5618-5630|