Targeting LRP/LR for the treatment of metastatic lung and colorectal cancer through impediment of telomerase activity

School of Molecule and Cell Biology University of the Witwatersrand, Johannesburg 2018The 37 kDa/67 kDa laminin receptor (LRP/LR) plays a vital role in the malignancy of various cancer types contributing to invasion, adhesion, apoptosis evasion, proliferation and tumour angiogenesis. In addition, LRP/LR interacts with the catalytic reverse transcriptase subunit, TERT, of the ribonucleoprotein telomerase. Both LRP/LR and telomerase are implicated in cancer progression and knockdown of LRP/LR causes a decrease in telomerase activity in breast cancer cells. In the current study, LRP/LR was downregulated in lung adenocarcinoma (A549) and late-stage colorectal carcinoma (DLD-1) cells in an attempt to impede telomerase activity and ultimately impede cancer progression. Western blotting analysis showed a significant decrease in LRP/LR levels in HEK293 (Human Embryonic Kidney Cells) and A549 cells after siRNA mediated LRP/LR knockdown. To confirm LRP/LR knockdown confocal microscopy was performed; a reduction in LRP/LR protein levels was observed which also resulted in a subsequent decrease in hTERT mRNA levels with a corresponding decrease in hTERT levels in HEK293, A549, and DLD-1 cell lines. Furthermore, siRNA mediated knockdown of LRP/LR significantly decreased telomerase activity in HEK293, A549, and DLD-1 cells. The effect of LRP/LR downregulation on cellular viability was investigated via the MTT assay and a significant decrease in cell viability in A549 and DLD-1 cells was observed. Since downregulation of LRP/LR impedes telomerase activity and decreases cell viability, siRNAs directed against LRP mRNA acts as potential alternative therapeutic tools for treatment of lung adenocarcinoma and late-stage colorectal carcinoma.XL201