Abstract
Novel biomarkers for cancer diagnosis and therapy selection are urgently needed to facilitate early detection and improve therapy outcomes. We have previously identified a novel phosphorylation site at serine 506 (PS506) on topoisomerase-I (topo-I) and have shown that it is widely expressed in cell lines derived from several cancers, including lung cancer, but is low in cell lines derived from non-cancerous tissues. Here we have investigated how PS506 expression in lung tissue specimens correlates with their malignant status. We find that PS506 expression is significantly elevated in malignant tumors of non-small cell lung cancer (NSCLC) compared to adjacent, non-cancerous lung tissue and benign lung tumors. PS506 expression was up to 6-fold higher in malignant specimens than in paired non-malignant tissue. Using the well-characterized NIH/NCI 60-cell line panel, we correlate the most elevated expression levels of PS506 in lung, ovarian, and colon cancer cells lines with increased sensitivity to camptothecin, a plant alkaloid that targets topo-I. This is consistent with our earlier studies in a smaller sampling of cell lines and with our finding that PS506 increases topo-I DNA binding. Two widely used chemotherapeutic drugs for ovarian and colon cancer, topotecan and irinotecan, respectively, are derived from camptothecin. Irinotecan has also displayed efficacy in clinical trials of NSCLC. Our results suggest that elevated PS506 expression may correlate with clinical chemosensitivity to these agents in ovarian, colon, and NSCLC. PS506 may therefore serve as a biomarker for diagnosis or therapy selection.
Highlights
New molecular biomarkers for cancer, those relevant to the mechanism of cancer or to cancer therapy, could enhance the power of currently used diagnostic approaches, reduce the risk of over diagnosis, facilitate treatment selection, and greatly improve cancer survival
This study demonstrates that expression of phosphorylation site at serine 506 (PS506) is malignancy-specific, and that the highest levels of PS506 expression in cancer cell lines of lung, colon, and ovarian cancer origin correlate with increased sensitivity to CPT
PS506 levels were elevated in all 21 malignant specimens of non-small cell lung cancer compared to paired non-malignant tissue and to 8 benign lung tumor specimens
Summary
New molecular biomarkers for cancer, those relevant to the mechanism of cancer or to cancer therapy, could enhance the power of currently used diagnostic approaches, reduce the risk of over diagnosis, facilitate treatment selection, and greatly improve cancer survival. We have previously identified a novel phosphorylation site on topoisomerase I (topo I) at serine residue 506 (PS506) that is highly expressed in cancer-derived cell lines but is low to undetectable in cell lines derived from normal tissues, making it a possible candidate as a malignancy-associated biomarker for diagnosis [1]. Increased topo I phosphorylation occurs in many cancerderived cell lines and correlates with expression of PS506 in the core domain of the protein [8, 9]. We found that PS506 expression correlates with increased levels of the serine-threonine protein kinase, CK2, and that recombinant topo I can be phosphorylated on serine 506 by purified CK2 [1]. Aberrant expression of PS506 may be symptomatic of the pro-oncogenic environment created by elevated CK2
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