TOP1 modulation during melanoma progression and in adaptative resistance to BRAF and MEK inhibitors

Abstract

In melanomas, therapy resistance can arise due to a combination of genetic, epigenetic and phenotypic mechanisms. Due to its crucial role in DNA supercoil relaxation, TOP1 is often considered an essential chemotherapeutic target in cancer. However, how TOP1 expression and activity might differ in therapy sensitive versus resistant cell types is unknown. Here we show that TOP1 expression is increased in metastatic melanoma and correlates with an invasive gene expression signature. More specifically, TOP1 expression is highest in cells with the lowest expression of MITF, a key regulator of melanoma biology. Notably, TOP1 and DNA Single-Strand Break Repair genes are downregulated in BRAFi-and BRAFi/MEKiresistant cells and TOP1 inhibition decreases invasion markers only in BRAFi/MEKiresistant cells. Thus, we show three different phenotypes related to TOP1 levels: i) nonmalignant cells with low TOP1 levels; ii) metastatic cells with high TOP1 levels and high invasiveness; and iii) BRAFi-and BRAFi/MEKi-resistant cells with low TOP1 levels and high invasiveness. Together, these results highlight the potential role of TOP1 in melanoma progression and resistance.

Venlafaxine, an anti-depressant drug, induces apoptosis in MV3 human melanoma cells through JNK1/2-Nur77 signaling pathway

“…In addition, the MERK/ERK pathway plays a critical role in inducing Nur77 expression. GnRH promoted Nur77 expression in alpha T3-1 cells through ERK signaling ( Bliss et al, 2012 ; Oliveira et al, 2021 ; Liu Y. X et al, 2022 ). Scalarane sesterterpenoid 12-deacetyl-12-epi-scalaradial induces HeLa cells apoptosis through ERK-mediated expression and phosphorylation of Nur77 ( Zhou et al, 2020 ).…”

Isovalerylspiramycin I inhibits proliferation, migration and invasion of osteosarcoma cells by targeting Topoisomerase 1 and suppressing the ataxia telangiectasia and Rad3‐related/checkpoint kinase 1 pathway

“…Thus, DNA topoisomerase inhibitors are potential anticancer agents because they help maintain strand breaks generated during replication by topoisomerases 5 . In fact, anticancer agents targeting topoisomerase I (TOP1) and II (TOP2) have been widely used in cancer treatment 6–9 . For OS, the TOP2 inhibitor adriamycin (ADM) is one of the most effective chemotherapeutic agents 10 .…”

“…5 In fact, anticancer agents targeting topoisomerase I (TOP1) and II (TOP2) have been widely used in cancer treatment. [6][7][8][9] For OS, the TOP2 inhibitor adriamycin (ADM) is one of the most effective chemotherapeutic agents. 10 In contrast, conventional TOP1 inhibitors such as irinotecan, topotecan, and camptothecin, have shown limited efficacy in OS and have rarely been used clinically 11,12 despite frequent TOP1 gene alterations in OS.…”

QUALITY BY DESIGN APPROACH FOR DEVELOPMENT AND OPTIMIZATION OF CHITOSAN-BASED FLOATING MICROSPHERES FOR TOPOTECAN HCl

“…Usually, anti-cancer drugs help in inhibiting the cancer cells either by blemishing the ribonucleic acid (RNA) or by blemishing the deoxyribonucleic acid (DNA), which is very much required for the cell division of cancer cells [2]. The mechanism of TPT involves encouraging the formation of fatal double-stranded DNA instead of single-stranded DNA during the S-phase of the cell cycle by hindering the required Topoisomerase-I enzyme [3].…”