Lung cancer is the most common
malignancy and exhibits significant morbidity and mortality worldwide. Among all
lung cancer subtypes,
non-small-cell lung cancer (NSCLC) accounts for the majority of all
lung cancer cases. Although there have been intensive investigations on the underlying mechanism of NSCLC development and progression, the exact molecular basis is not well understood. Further insights on important molecular regulators of
lung cancer are needed for development of novel
therapeutics. The
heat shock protein (HSP) family is a group of
molecular chaperones that assist in protein folding, modification, and transportation. Different HSPs are essential for
tumor cell survival by binding diverse client
proteins and regulating homeostasis. In the current study, we sought to characterize HSP70 and HSP90 as potent regulators of NSCLC growth. Our results indicate that differential expression of HSP70 is associated with the malignant phenotype of NSCLC cell lines and plays an important regulatory role in NSCLC cell proliferation. Moreover, a specific inhibitor of HSP70,
VER-155008 significantly inhibits NSCLC proliferation and cell cycle progression. We showed that this effect is largely abolished by HSP70 overexpression, indicating that the inhibitory effect of
VER-155008 on cell growth is specifically through HSP70 inhibition. In addition, 17-AAD, an inhibitor of HSP90, exerts a potent synergistic effect on NSCLC proliferation with
VER-155008. We also observed that inhibition of HSP70 by
VER-155008 can sensitize A549 cells to ionizing radiation. These data provide proof-of-principle that
VER-155008 can be a good candidate for NSCLC treatment and HSP machinery is a good target for developing NSCLC
therapeutics.