Over 100 years ago, the founder of chemotherapy, Paul Ehrlich, coined the term “magic bullet” to describe an ideal therapeutic agent used to target disease, such as cancer. Since then, we have assessed many different anti-tumorigenic compounds, although we are only beginning to understand just how some of these bullets hit their target.
This understanding, alongside helping us gain a broader appreciation of cancer biology, may also uncover brand new targets for drug development. Win-win.
While aspirin, or acetylsalicylic acid, is usually taken in response to pain and inflammation associated with rogue happy hours or given to thin the blood, regular use is also an effective treatment for colorectal cancer (CRC). A new paper published in Genome Biology from Haiyan Guo, Wantao Chen, and Jianjun Zhang at Shanghai Jiao Tong University in China now demonstrates how aspirin functions – its hits the target with a little help from long non-coding RNA (lncRNA).
An initial microarray analysis found that aspirin treatment mediated the significant upregulation of OLA1P2 lncRNA expression in a CRC cell line. The authors then went fishing, using the promoter sequence of OLA1P2 as bait to catch any transcription factors present in a CRC nuclear extract that may upregulate OLA1P2 expression.
One-shot mass spectrometry analysis of the factors captured in the pull-down assay brought home FOXD3 as the catch of the day, and the authors soon worked out that aspirin treatment demethylated the promoter region of FOXD3, leading to its upregulation and, thereby, upregulation of OLA1P2
But how does OLA1P2 upregulation reduce tumorigenesis? OLA1P2 knockdown in CRC cells suggested the involvement of the STAT3 signaling pathway, although the study found no obvious differences in STAT3 mRNA or protein levels. They did find that OLA1P2 interacts with phosphorylated STAT3 to inhibit its dimerization and translocation from the cytoplasm into the nucleus, thus inhibiting the transcription of STAT3 target genes.
Finally, the study also demonstrated that OLA1P2 expression in CRC cells inhibited both tumorigenesis and metastasis and furthermore, that aspirin’s anti-tumorigenic effect weakened in cells where OLA1P2 was absent. They also underlined the clinical relevance of these findings by showing that higher levels of OLA1P2 in aspirin-treated patient samples correlated with lower tumor progression and better survival.
This exciting new study not only delineates just how aspirin hits the target as an anti-tumorigenic agent but also may provide us with brand new targets to treat CRC tumors. However, the authors note that OLA1P2 overexpression also occurs in other tumors, so long-term aspirin treatment may provide benefits to patients suffering from oral, gastric, and colon cancer.
Check out how this magic bullet hits the target at Genome Biology, February 2016.