TY - JOUR
T1 - TOP1 modulation during melanoma progression and in adaptative resistance to BRAF and MEK inhibitors
AU - Oliveira, Érica Aparecida de
AU - Chauhan, Jagat
AU - Silva, Julia Rezende da
AU - Carvalho, Larissa Anastacio da Costa
AU - Dias, Diogo
AU - Carvalho, Danielle Gonçalves de
AU - Watanabe, Luis Roberto Masao
AU - Rebecca, Vito W.
AU - Mills, Gordon
AU - Lu, Yiling
AU - da Silva, Aloisio Souza Felipe
AU - Consolaro, Márcia Edilaine Lopes
AU - Herlyn, Meenhard
AU - Possik, Patricia A.
AU - Goding, Colin R.
AU - Maria-Engler, Silvya Stuchi
N1 - Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/11
Y1 - 2021/11
N2 - 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/MEKi-resistant cells and TOP1 inhibition decreases invasion markers only in BRAFi/MEKi-resistant cells. Thus, we show three different phenotypes related to TOP1 levels: i) non-malignant 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.
AB - 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/MEKi-resistant cells and TOP1 inhibition decreases invasion markers only in BRAFi/MEKi-resistant cells. Thus, we show three different phenotypes related to TOP1 levels: i) non-malignant 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.
KW - MITF
KW - Melanoma
KW - Resistance
KW - TOP1
KW - Topotecan
UR - http://www.scopus.com/inward/record.url?scp=85116026655&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85116026655&partnerID=8YFLogxK
U2 - 10.1016/j.phrs.2021.105911
DO - 10.1016/j.phrs.2021.105911
M3 - Article
C2 - 34560251
AN - SCOPUS:85116026655
SN - 1043-6618
VL - 173
JO - Pharmacological Research
JF - Pharmacological Research
M1 - 105911
ER -