Knock-Down of the 37kDa/67kDa Laminin Receptor LRP/LR Impedes Telomerase Activity

Abstract

Cancer has become a major problem worldwide due to its increasing incidence and mortality rates. Both the 37kDa/67kDa laminin receptor (LRP/LR) and telomerase are overexpressed in cancer cells. LRP/LR enhances the invasiveness of cancer cells thereby promoting metastasis, supporting angiogenesis and hampering apoptosis. An essential component of telomerase, hTERT is overexpressed in 85–90% of most cancers. hTERT expression and increased telomerase activity are associated with tumor progression. As LRP/LR and hTERT both play a role in cancer progression, we investigated a possible correlation between LRP/LR and telomerase. LRP/LR and hTERT co-localized in the perinuclear compartment of tumorigenic breast cancer (MDA_MB231) cells and non-tumorigenic human embryonic kidney (HEK293) cells. FLAG® Co-immunoprecipitation assays confirmed an interaction between LRP/LR and hTERT. In addition, flow cytometry revealed that both cell lines displayed high cell surface and intracellular LRP/LR and hTERT levels. Knock-down of LRP/LR by RNAi technology significantly reduced telomerase activity. These results suggest for the first time a novel function of LRP/LR in contributing to telomerase activity. siRNAs targeting LRP/LR may act as a potential alternative therapeutic tool for cancer treatment by (i) blocking metastasis (ii) promoting angiogenesis (iii) inducing apoptosis and (iv) impeding telomerase activity.

Knockdown of LRP/LR induces apoptosis in pancreatic cancer and neuroblastoma cells through activation of caspases

“…Therefore, it is evident that LRP/LR is crucial for metastatic processes and is a promising target for metastatic cancer therapeutics. In addition to metastasis, LRP/LR is also suggested to enhance tumour angiogenesis [26] and recently Naidoo et al [27] and Otgaar et al [28] elucidated a novel role for LRP/LR in mediating telomerase activity through the enhancement of hTERT activity. In particular, knock-down of LRP/LR resulted in impediment of telomerase activity in metastatic breast cancer cells, combating the pro-tumourigenic activities of LRP/LR [27].…”

“…In addition to metastasis, LRP/LR is also suggested to enhance tumour angiogenesis [26] and recently Naidoo et al [27] and Otgaar et al [28] elucidated a novel role for LRP/LR in mediating telomerase activity through the enhancement of hTERT activity. In particular, knock-down of LRP/LR resulted in impediment of telomerase activity in metastatic breast cancer cells, combating the pro-tumourigenic activities of LRP/LR [27]. Very recently, we showed that LRP::FLAG enhances telomerase activity concomitant with reduced senescence markers, indicating that LRP plays a profound role in the ageing process [28].…”

Knock-Down of LRP/LR Influences Signalling Pathways in Late Stage Colorectal Carcinoma Cells

“…In addition to LRP/LR's roles in cancer, the receptor has been found to contribute to telomerase activity in breast cancer cells [30]. Telomerase is a ribonucleoprotein with reverse transcriptase activity principally responsible for maintaining and elongating telomeres; tandem TTAGGG repeats found on the ends of chromosomes which help prevent chromosomal degradation [31].…”

“…More importantly, that the two proteins have interlinked roles in various diseases such as cancer and neurodegenerative disorders [38]. Naidoo et al (2015) showed that telomerase and LRP/LR co-localize in the perinuclear compartment of breast cancer cells [30] and it has recently been found that LRP/LR enhances telomerase activity [12,14]. Moreover, additional studies have revealed that the knock-down of LRP/LR signi cantly reduces telomerase activity [30,39].…”

Anti-LRP/LR-Specific Antibody IgG1-iS18 Significantly Impedes Adhesion and Invasion in Early- and Late-Stage Colorectal Carcinoma Cells

“…LRP/LR has been found to be a major contributor to the pathogenesis of neoplastic cancers (10), angiogenesis enhancement (12), prion disorders (13)(14)(15) and neurodegenerative diseases such as Alzheimer's disease (16)(17)(18)(19)(20). In addition, upregulation of the receptor has been seen to be implicated in telomerase activity (21). Research has shown that LRPmRNA encodes for the 37kDa laminin receptor precursor, which is the precursor protein for the 67kDa high-affinity laminin receptor (22).…”