Abstract
Heat shock proteins (HSPs) are a large group of chaperones considered critical for maintaining cellular proteostasis. Their aberrant expression in tumors can modulate the course of processes defined as hallmarks of cancer. Previously, we showed that both stress-inducible HSPA1 and testis-enriched HSPA2, highly homologous members of the HSPA (HSP70) family, are often overexpressed in non-small cell lung carcinoma (NSCLC). HSPA1 is among the best characterized cancer-related chaperones, while the significance of HSPA2 for cancer remains poorly understood. Previously we found that in primary NSCLC, HSPA1 was associated with good prognosis while HSPA2 correlated with bad prognosis, suggesting possible different roles of these proteins in cancer. Therefore, in this work we investigated the impact of HSPA1 and HSPA2 on NSCLC cell phenotype. We found that neither paralog-selective nor simultaneous knockdown of HSPA1 and HSPA2 gene expression reduced growth and chemoresistance of NSCLC cells. Only blocking of HSPA proteins using pan-HSPA inhibitors, VER-155008 or JG-98, exerted potent anticancer effect on NSCLC cells, albeit the final outcome was cell type-dependent. Pan-HSPA inhibition sensitized NSCLC cells to bortezomib, but not to platinum derivates. Our result suggests the inhibitors of proteasome and HSPAs seem an effective drug combination for pre-clinical development in highly aggressive NSCLC.
Highlights
The observation that the pattern of Heat shock proteins (HSPs) expression can alter during tumor development initiated a number of studies aimed at clarifying a potential predictive and prognostic value of HSPs7,8
Bearing in mind that HSPA1 and HSPA2 can be expressed in non-small cell lung carcinoma (NSCLC) cells either together or separately and may have a different prognostic value, we found important to study the influence of both proteins on proliferation rate and chemoresistance of NSCLC cells to CDDP and BTZ
We analyzed the expression of the HSPA family member, namely HSPA1, HSPA2 and HSPA8, cytosolic/nuclear chaperones and HSPA5, the endoplasmic reticulum-located, as well as HSPC (HSP90) protein in CDDP-resistant (NCI-H1299, NCI-H358, NCI-H520) and CDDP-sensitive (Beas-2B, NCI-H23) cell lines (Fig. 1A,B)
Summary
The observation that the pattern of HSPs expression can alter during tumor development initiated a number of studies aimed at clarifying a potential predictive and prognostic value of HSPs7,8. In our earlier studies we found that prognostic values of HSPA2 and HSPA1 expression in patients with primary non-small cell lung carcinoma (NSCLC) are opposite. Our findings correspond well to results showing negative prognostic value of a decreased expression of HSPA1 in small cell lung carcinoma[25], or association between a high level of HSPA1 and longer disease-free survival of NSCLC patients who received adjuvant platinum-based chemotherapy[26]. In vitro studies showed that BTZ can potentiate the anticancer effect of cisplatin (CDDP) on various NSCLC cell lines, what encourages further investigations[27,28,29]. Studies aimed at understanding the impact of HSPs on the effectives of lung cancer treatment have concentrated on the HSP90 (HSPC) protein, mainly due to development of multiple inhibitors. As for HSPA2, its potential impact on growth and resistance to CDDP, BTZ and other anticancer drugs has not been tested in NSCLC cells
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