Influence of metformin on HIF-1 pathway in multiple myeloma
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Influence of metformin on HIF‑1 pathway in multiple myeloma Kinga A. Kocemba‑Pilarczyk1 · Sonia Trojan1 · Barbara Ostrowska1 · Małgorzata Lasota2 · Paulina Dudzik1 · Dorota Kusior1 · Marta Kot2 Received: 10 February 2019 / Revised: 15 July 2020 / Accepted: 15 July 2020 © The Author(s) 2020
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. Keywords Metformin · Multiple myeloma · HIF-1 pathway
Introduction Multiple myeloma (MM), is one of the most common hematological malignancies described as a clonal expansion of plasma cells in the bone marrow associated with pancytopenia, renal failure and osteolytic bone disease. During the progression of the disease the MM cells are fully dependent on the bone marrow environment which comprises growth and survival factors for developing tumors. Interestingly, recent studies revealed that insufficient oxygenation in MM infiltrated bone marrow constitutes an important factor * Kinga A. Kocemba‑Pilarczyk [email protected] 1
Medical Biochemistry, Jagiellonian University-Medical College, ul. Kopernika 7, 31‑034 Kraków, Poland
Department of Transplantation, Jagiellonian University Medical College, Kraków, Poland
2
enhancing the aggressiveness of this malignancy [1]. In particular, hypoxia in MM was reported to enhance tumor initiation, upregulate genes expressed at the immatur
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