MnTE-2-PyP reduces prostate cancer growth and metastasis by suppressing p300 activity and p300/HIF-1/CREB binding to the promoter region of the PAI-1 gene

Abstract

To improve radiation therapy-induced quality of life impairments for prostate cancer patients, the development of radio-protectors is needed. Our previous work has demonstrated that MnTE-2-PyP significantly protects urogenital tissues from radiation-induced damage. So, in order for MnTE-2-PyP to be used clinically as a radio-protector, it is fully necessary to explore the effect of MnTE-2-PyP on human prostate cancer progression. MnTE-2-PyP inhibited prostate cancer growth in the presence and absence of radiation and also inhibited prostate cancer migration and invasion. MnTE-2-PyP altered p300 DNA binding, which resulted in the inhibition of HIF-1β and CREB signaling pathways. Accordingly, we also found that MnTE-2-PyP reduced the expression of three genes regulated by HIF-1β and/or CREB: TGF-β2, FGF-1 and PAI-1. Specifically, MnTE-2-PyP decreased p300 complex binding to a specific HRE motif within the PAI-1 gene promoter region, suppressed H3K9 acetylation, and consequently, repressed PAI-1 expression. Mechanistically, less p300 transcriptional complex binding is not due to the reduction of binding between p300 and HIF-1/CREB transcription factors, but through inhibiting the binding of HIF-1/CREB transcription factors to DNA. Our data provide an in depth mechanism by which MnTE-2-PyP reduces prostate cancer growth and metastasis, which validates the clinical use of MnTE-2-PyP as a radio-protector to enhance treatment outcomes in prostate cancer radiotherapy.

MnTE-2-PyP modulates thiol oxidation in a hydrogen peroxide-mediated manner in a human prostate cancer cell

“…We have previously published that MnTE-2-PyP suppresses PAI-1 expression regulated by the p300/HIF-1β and/or CREB complex with or without 20 Gy irradiation [13]. Because we wanted to determine changes right after irradiation, we used a radiation dose of 20 Gy to aid in observing larger differences between the unirradiated and irradiated cells.…”

“…We have also previously shown that MnTE-2-PyP reduces p300 binding to the HRE binding site on the PAI-1 promoter [13]. We performed a p300 ChIP-qPCR assay to test the binding of the p300 complex to the identified PAI-1 gene promoter region.…”

“…showed that in combination with radiation, MnTE-2-PyP inhibits both tumor growth and tumor angiogenesis in mouse mammary cancer cells [12]. MnTE-2-PyP also sensitizes human prostate cells to radiation [13]. Thus, these reports above demonstrate that MnTE-2-PyP could be used clinically as a radioprotector and radiosensitizer for the treatment of cancer radiotherapy.…”

“…In that study, we determined that MnTE-2-PyP decreased p300/HIF-1/CREB complex (p300/hypoxia-inducible factor-1/cAMP response element-binding protein) binding to a specific hypoxia-response element (HRE) motif within the plasminogen activator inhibitor-1 (PAI-1) gene promoter region, suppressed H3K9 acetylation, and as a result repressed PAI-1 expression [13]. However, we still do not understand the mechanism by which MnTE-2-PyP reduces the p300 complex binding affinity for the promoter region of PAI-1.…”

MnTnBuOE-2-PyP protects normal colorectal fibroblasts from radiation damage and simultaneously enhances radio/chemotherapeutic killing of colorectal cancer cells

“…Manganese porphyrins have been shown to inhibit HIF-1β and NF-κB, two pathways that tumors exploit to promote survival and progression of the cancer cell [47, 51, 52]. Therefore, one explanation for how MnTnBuOE-2-PyP may be inhibiting cancer growth is through the inhibition of these two pathways.…”