Heme oxygenase 1 counteracts pro-stemness and pro-invasive effect triggered by communication with bone progenitors in prostate cancer cells

INES ACHINELLI; AGUSTINA SABATER; PABLO SANCHIS; NICOLAS ANSELMINO; SOFIA LAGE VICKERS; GASTON PASCUAL; ROCIO SENIUK; PAMELA FREIRIA; JAVIER COTIGNOLA; ELBA VAZQUEZ; MARIA SOL RUIZ; GERALDINE GUERON; AYELEN TORO

Simposio; 11th Annual Symposium on Global Cancer Research; 2023

PurposeMortality in prostate cancer (PCa) patients is mostly associated with bone metastasis and aggressive phenotypes promoted by prostate cancer stem cells (PCSCs). We have previously described that heme oxygenase 1 (HO-1), the rate-limiting enzyme in heme catabolism with antioxidant and antiinflammatory properties, presents an antitumoral role in PCa. In this work, we assessed the role of HO-1 as a modulator of stemness and metastasis associated genes in PCa cells conditioned by bone progenitor cells.MethodsAn indirect transwell co-culture system of PC3 cells, a PCa cell line, with MC3T3 cells, an osteoblast precursor cell line, was developed as an in vitro model of PCa bone metastasis. Additionally, PC3 cells were pre-treated with hemin, a pharmacological HO-1 inductor. An RNA-seq was performed to analyze the transcriptome of PC3 cells. The expression of a curated list of 87 genes associated with stemness, metastasis and the STAT3 pathway, including PCSC and classic pluripotency markers, together with a gene signature previously described by our group (ADAM15, BCL2L1, LTBR, MBNL2, SPINT1), was assessed. Results were complemented with survival data of PCa patients (TCGA-PRAD, n=565).ResultsOur results showed that PC3 cells co-cultured with MC3T3 cells displayed an upregulation of PCSC markers CD44, ALDH1A3 and ALDH1L2, pluripotency markers OCT4 and SOX2, and BCL2L1 and LTBR, two genes included in our signature, compared with non-co-cultured PC3 cells. Further, when comparing co-cultured PC3 cells vs. co-cultured PC3 cells pre-treated with hemin, in the latter group the expression of 71/87 genes associated with stemness, metastasis and STAT3 pathway decreased, including CD44, ALDH1A3, ALDH1L2, OCT4, MBNL2 and ADAM15. Moreover, when evaluating patients’ disease progression free survival, those with high expression of OCT4 showed a lower risk of the event.ConclusionHO-1 expression modulates stemness and metastasis related genes in PCa, promoting a more differentiated state, counteracting the pro-stemness effect of communication with bone progenitors. This further supports the antitumoral role of HO-1 in PCa pointing out to its potential as a therapeutic target for the disease.