Progesterone at high doses reduces the growth of U87 and A172 glioblastoma cells: Proteomic changes regarding metabolism and immunity

Abstract

While pregnancy may accelerate glioblastoma multiforme (GBM) growth, parity and progesterone (P4) containing treatments (ie, hormone replacement therapy) reduce the risk of GBM development. In parallel, low and high doses of P4 exert stimulating and inhibitory actions on GBM growth, respectively. The mechanisms behind the high‐dose P4‐suppression of GBM growth is unknown. In the present study, we assessed the changes in growth and proteomic profiles when high‐dose P4 (100 and 300 µM) was administered in human U87 and A172 GBM cell lines. The xCELLigence system was used to examine cell growth when different concentrations of P4 (20, 50, 100, and 300 µM) was administered. The protein profiles were determined by two‐dimensional gel electrophoresis in both cell lines when 100 and 300 µM P4 were administered. Finally, the pathways enriched by the differentially expressed proteins were assessed using bioinformatic tools. Increasing doses of P4 blocked the growth of both GBM cells. We identified 26 and 51 differentially expressed proteins (fc > 2) in A172 and U87 cell lines treated with P4, respectively. Only the pro‐tumorigenic mitochondrial ornithine aminotransferase and anti‐apoptotic mitochondrial 60 kDa heat shock protein were downregulated in A172 cell line and U87 cell line when treated with P4, respectively. Detoxification of reactive oxygen species, cellular response to stress, glucose metabolism, and immunity‐related proteins were altered in P4‐treated GBM cell lines. The paradox on the effect of low and high doses of P4 on GBM growth is gaining attention. The mechanism related to the high dose of P4 on GBM growth can be explained by the alterations in detoxification mechanisms, stress, and immune response and glucose metabolism. P4 suppresses GBM growth and as it is nontoxic in comparison to classical chemotherapeutics, it can be used as a new strategy in GBM treatment in the future.

Specific Compositions of Cannabis sativa Compounds Have Cytotoxic Activity and Inhibit Motility and Colony Formation of Human Glioblastoma Cells In Vitro

“…Interestingly, U87 cells were less sensitive to the cytotoxic effect of F4 or F5 but more sensitive to the F4 effect on sphere formation in comparison to A172 cells. U87 and A172 are GBM cell lines that harbor different genetic mutations [ 54 , 55 ]. For example, A172 cells carry a p53 mutation, whereas U87 cells express a wild-type p53.…”

“…A172 cells are incapable of invading de-epithelialized tracheas, whereas U87 cells do so via increased activity of matrix metalloprotease-3 (MMP-3). In addition, A172 and U87 differ to some extent in their tumorigenic activity in immunosuppressed mice and their response to progesterone (P4) [ 54 , 55 ]. It is possible that the differences between U87 and A172 cells identified here are a result of their different genetic background.…”

Astrocytoma: A Hormone-Sensitive Tumor?

“…The anti-proliferative effects of high doses of progesterone would be due to a slowdown of glycolytic metabolism in these cell lines [75]. Recently, Altinoz and colleagues [76] explored the proteomic changes in U87 and A172 human GBM cells treated by 100 µM or 300 µM progesterone: detoxification of reactive oxygen species, cellular response to stress, glucose metabolism, and immunity-related proteins were affected by these high doses of progesterone, leading to a slowdown of cell proliferation [76].…”

Impact of sex in the prevalence and progression of glioblastomas: the role of gonadal steroid hormones

“…Antiproliferative effects of high concentrations of P4 have been related to the reduction of glycolytic metabolism and the induction of cell senescence by decreasing the Glut1 expression and attenuating the signaling pathway PI3K/Akt/mTOR [ 15 ]. A recent proteomic analysis, conducted by Altinoz and cols suggests that suppressive actions of high doses of P4 on glioblastoma are induced by changes in detoxification mechanisms, stress, immune response, and glucose metabolism [ 13 ]. High doses of medroxyprogesterone acetate, a synthetic variant of P4, have also shown antiproliferative effects on glioblastoma-derived cell lines such as C6 and U87 [ 72 ].…”

“…-Changes in detoxification mechanisms, stress, immune response, and glucose metabolism (100 and 300 μM) (ref [13])…”