Members of FOX family could be drug targets of cancers.

The MYC oncoprotein functions as a master regulator of cellular transcription and executes non-transcriptional tasks relevant to DNA replication and cell cycle regulation, thereby interacting with multiple proteins. MYC is required for fundamental cellular processes triggering proliferation, growth, differentiation, or apoptosis and also represents a major cancer driver being aberrantly activated in most human tumors. Due to its non-enzymatic biochemical functions and largely unstructured surface, MYC has remained difficult for specific inhibitor compounds to directly address, and consequently, alternative approaches leading to indirect MYC inhibition have evolved. Nowadays, multiple organic compounds, nucleic acids, or peptides specifically interfering with MYC activities are in preclinical or early-stage clinical studies, but none of them have been approved so far for the pharmacological treatment of cancer patients. In addition, specific and efficient delivery technologies to deliver MYC-inhibiting agents into MYC-dependent tumor cells are just beginning to emerge. In this review, an overview of direct and indirect MYC-inhibiting agents and their modes of MYC inhibition is given. Furthermore, we summarize current possibilities to deliver appropriate drugs into cancer cells containing derailed MYC using viral vectors or appropriate nanoparticles. Finding the right formulation to target MYC-dependent cancers and to achieve a high intracellular concentration of compounds blocking or attenuating oncogenic MYC activities could be as important as the development of novel MYC-inhibiting principles.

https://www.frontiersin.org/articles/10.3389/fonc.2023.1142111/pdf

Strategies to target the cancer driver MYC in tumor cells

At various stages of ovarian follicular development, more than 99% of follicles will be eliminated through a degenerative process called atresia. The regulatory mechanisms of atresia have been elucidated to some extent, involving hormones, growth factors, cytokines, and other factors. However, the stimuli initiating atresia in follicular granulosa cells remain unknown. In this study, we isolated the granulosa cells from porcine ovarian follicles (3-5 mm diameter) divided into healthy follicles (HFs) and early atretic follicles (EAFs). We applied high-throughput RNA sequencing to identify and compare differentially expressed genes (DEGs) between HFs and EAFs. A total of 31,694 genes were detected, of which 21,806 were co-expressed in six samples, and 243 genes (p < 0.05; FDR < 0.05) were differentially expressed (DEGs), including 123 downregulated and 120 upregulated in EAFs. GO analysis highlighted hormone metabolism, plasma membrane localization, and transporter activity. The pathway analysis indicated that 51 DEGs, involved in steroidogenesis, cell adhesion molecules, and TGF-beta signaling pathways, were highly related to atresia. Additionally, the interaction network of DEGs (p < 0.01; FDR < 0.05) using STRING highlighted LHR, ACACB, and CXCR4 as central nodes. In summary, this transcriptome analysis enriched our knowledge of the shifted mechanisms in granulosa cells during early atresia and provided novel perspectives into the atresia initiation.

Comparative transcriptome profile analysis of granulosa cells from porcine ovarian follicles during early atresia.

Pancreatic cancer is usually diagnosed in the advanced stages and is sensitive to only few therapies. The forkhead box L1 (FOXL1) and protein phosphatase 2A (PP2A) have been recognized to be tumor suppressive in human pancreatic cancers. In the present study, we co-expressed the two tumor suppressive molecules with a '2A peptide' linker, which guaranteed the two molecules were transcribed into one mRNA, whereas they were translated into two separate proteins, in pancreatic cancer Panc‑1 cells, and investigated the inhibition of the two molecules on the proliferation and migration of Panc‑1 cells. Results demonstrated that, either overexpression of FOXL1 or PP2A via adenovirus significantly inhibited the proliferation of Panc‑1 cells, whereas promoted apoptosis in such cells. Moreover, the co-expression of both FOXL1 and PP2A exerted synergistic antitumor effect in Panc‑1 cells, with significantly higher proliferation inhibition and tumor induction. In addition, we found that the overexpressed FOXL1 promoted the TNF‑related apoptosis‑inducing ligand (TRAIL), whereas the overexpressed PP2A downregulated the phosphorylation of c‑MYC. The co-expression of FOXL1 and PP2A presented both functions in Panc‑1 cells. In conclusion, the adenovirus‑mediated co‑expression of FOXL1 and PP2A with the 2A peptide linker exterts synergistic suppression of pancreatic cancer cells via inhibiting the growth and promoting apoptosis of cancer cells, probably via upregulating TRAIL and reducing the phosphorylation of MYC.

/pdf/co-expression-of-foxl1-and-pp2a-inhibits-proliferation-4an5h0tlwv.pdf

Co-expression of FOXL1 and PP2A inhibits proliferation inducing apoptosis in pancreatic cancer cells via promoting TRAIL and reducing phosphorylated MYC.

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Co-expression of FOXL1 and PP2A inhibits proliferation inducing apoptosis in pancreatic cancer cells via promoting TRAIL and reducing phosphorylated MYC.