Bortezomib represses HIF-1α protein expression and nuclear accumulation by inhibiting both PI3K/Akt/TOR and MAPK pathways in prostate cancer cells

Abstract

Bortezomib represents the first proteasome inhibitor (PI) with demonstrated antitumor activity in the clinical setting, particularly for treatment of hematological malignancies. At the preclinical level, its action is shown to be mediated by induction of growth arrest and apoptosis in many tumor types, including androgen-dependent (AD) and androgen-independent (AI) prostate cancer (PCa) cells. Hypoxia-inducible factor-1α (HIF-1α), which is directly involved in tumor growth, is one of the most studied and promising molecular targets for anti-cancer therapy and is often overexpressed in PCa. Bortezomib has been reported to impair tumor growth by also inhibiting HIF-1α. In this study, we investigated the effect of bortezomib on the expression, activity and localization of HIF-1α in LNCaP (AD) and PC3 (AI) PCa cells. First, we show that hypoxic upregulation of HIF-1α protein levels and activity involves both the PI3K/Akt/mTOR and p44/42 MAPK pathways. Second, bortezomib inhibits expression of HIF-1α protein under both normoxic and hypoxic conditions, represses HIF-1 transcriptional activity and attenuates the release of vascular endothelial growth factor. These effects correlate with the ability of bortezomib to cause dephosphorylation of phospho-Akt, phospho-p70S6K, and phospho-S6RP, thus inactivating a pathway known to be required for HIF-1α protein expression at the translational level. Furthermore, bortezomib also abrogates p44/42 MAPK phosphorylation, which results to reduced nuclear translocation of HIF-1α. Taken together, these results suggest that bortezomib inhibits HIF-1α protein synthesis and its nuclear targeting through suppression of PI3K/Akt/mTOR and MAPK pathways, respectively, in both AD and AI PCa cells.

p70S6 kinase is a target of the novel proteasome inhibitor 3,3′-diamino-4′-methoxyflavone during apoptosis in human myeloid tumor cells

“…NF-κB signaling pathway), inhibition of angiogenesis and suppression of PI3K/Akt/mTOR and MAPK pathways [52,[56][57][58][59]. Moreover, bortezomib stimulates cytotoxicity through accumulation of reactive oxygen species (ROS) [60,61].…”

Synergistic Activity of Bortezomib and HDACi in Preclinical Models of B-cell Precursor Acute Lymphoblastic Leukemia via Modulation of p53, PI3K/AKT, and NF-κB

“…The synergistic induction of apoptosis in our models of BCP-ALL was associated with modulation of cell cycle, death receptor, JUN/MAPK, and PI3K/AKT pathways. These pathways have also been implicated either in combined or single agent activity of HDACi and proteasome inhibitors in other malignancies (9,13,16,43,44).…”

Low dose photodynamic-therapy induce immune escape of tumor cells in a HIF-1α dependent manner through PI3K/Akt pathway

“…In addition, this pathway contributes to maintaining the malignant phenotype of tumor cells [11][12][13][14]. Moreover, HIF-1α expression through PI3K/Akt pathway is associated with the tumor microenvironment [8].…”