Influence of metformin on HIF-1 pathway in multiple myeloma

Abstract

Background Multiple myeloma (MM) is defined as plasma cells malignancy, developing in the bone marrow. At the beginning of the disease, the malignant plasma cells are dependent on bone marrow microenvironment, providing growth and survival factors. Importantly, the recent studies pointed hypoxia as an important factor promoting progression of MM. In particular, hypoxia-triggered HIF-1 signaling was shown to promote chemoresistance, angiogenesis, invasiveness and induction of immature phenotype, suggesting that strategies targeting HIF-1 may contribute to improvement of anti-myeloma therapies. Methods The Western Blot and RT-PCR techniques were applied to analyze the influence of metformin on HIF-1 pathway in MM cells. To evaluate the effect of metformin on the growth of MM cell lines in normoxic and hypoxic conditions the MTT assay was used. The apoptosis induction in metformin treated hypoxic and normoxic cells was verified by Annexin V/PI staining followed by FACS analysis. Results Our results showed, for the first time, that metformin inhibits HIF-1 signaling in MM cells. Moreover, we demonstrated the effect of metformin to be mainly oxygen dependent, since the HIF-1 pathway was not significantly affected by metformin in anoxic conditions as well as after application of hypoxic mimicking compound, CoCl2. Our data also revealed that metformin triggers the growth arrest without inducing apoptosis in either normoxic or hypoxic conditions. Conclusions Taken together, our study indicates metformin as a promising candidate for developing new treatment strategies exploiting HIF-1 signaling inhibition to enhance the overall anti-MM effect of currently used therapies, that may considerably benefit MM patients.

Disrupting Mitochondrial Electron Transfer Chain Complex I Decreases Immune Checkpoints in Murine and Human Acute Myeloid Leukemic Cells

“…Recent studies showed that CD39 expression was not induced by IFN-γ [ 59 , 60 ] whereas it can be induced under hypoxic conditions [ 61 , 62 ]. ETCI inhibitors have already been reported to interfere with HIF stabilization such as IACS [ 15 , 63 ] and metformin [ 64 , 65 , 66 ]. EVT-701 was also developed from a screening campaign to characterize HIF-1α inhibitors [ 22 ]; therefore, we propose an impairment of hypoxic signaling by interfering with HIF-1α stabilization as the mechanism by which EVT-701 decreases CD39 expression.…”

DNA Damage Response in Multiple Myeloma: The Role of the Tumor Microenvironment

“…HIF1-α directly binds to HREs on the proximal miR-210 promoter [ 152 , 153 ]. Furthermore, hypoxia-induced miR-210 increases the mRNA levels of VLA4 , CXCR4 , IL6 , and TGFB in MM cells [ 180 ]. miR-210 expression is significantly correlated with that of the hypoxia-inducible genes in myeloma cells [ 179 ].…”

Expression of Alternative Splice Variants of 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase-4 in Normoxic and Hypoxic Melanoma Cells

“…Western Blot analysis was performed as described previously [48]. Primary antibodies used were as follows: anti-HIF-1 alpha antibody (Cell Signaling Technology, Danvers, MA, USA, cat.…”