Jerantinine A induces tumor-specific cell death through modulation of splicing factor 3b subunit 1 (SF3B1)

Abstract

Precursor mRNA (pre-mRNA) splicing is catalyzed by a large ribonucleoprotein complex known as the spliceosome. Numerous studies have indicated that aberrant splicing patterns or mutations in spliceosome components, including the splicing factor 3b subunit 1 (SF3B1), are associated with hallmark cancer phenotypes. This has led to the identification and development of small molecules with spliceosome-modulating activity as potential anticancer agents. Jerantinine A (JA) is a novel indole alkaloid which displays potent anti-proliferative activities against human cancer cell lines by inhibiting tubulin polymerization and inducing G2/M cell cycle arrest. Using a combined pooled-genome wide shRNA library screen and global proteomic profiling, we showed that JA targets the spliceosome by up-regulating SF3B1 and SF3B3 protein in breast cancer cells. Notably, JA induced significant tumor-specific cell death and a significant increase in unspliced pre-mRNAs. In contrast, depletion of endogenous SF3B1 abrogated the apoptotic effects, but not the G2/M cell cycle arrest induced by JA. Further analyses showed that JA stabilizes endogenous SF3B1 protein in breast cancer cells and induced dissociation of the protein from the nucleosome complex. Together, these results demonstrate that JA exerts its antitumor activity by targeting SF3B1 and SF3B3 in addition to its reported targeting of tubulin polymerization.

A Challenging Pie to Splice: Drugging the Spliceosome

“…This, along with studies that advance a more detailed mechanistic understanding of the splicing process[35, 62] at both the single-gene and genome-wide levels, are key to advancing SPLMs into the clinic. [63]…”

Drug‐like dietary vanilloids induce anticancer activity through proliferation inhibition and regulation of bcl‐related apoptotic proteins

“…Conventional chemotherapy is often associated with nonselectivity in cancer proliferation, toxicity to noncancerous cells, intolerable adverse drug reaction, and drug resistance (Caponigro, Longo, Ionna, & Perri, ; Mohanty, Das, Kanwar, & Sahoo, ). To overcome this obstacle, natural isolated or semi‐synthetic drug‐like molecules have been investigated for potential anticancer properties (Chung et al, ; Mai, Wong, et al, ; Mai, Pakirisamy, et al, ; Mai et al, ; Soo et al, ; Wu, Ohnuma, & Ambudkar, ). Compounds with the functional group 4‐hydroxy‐3‐methoxyphenyl has great pharmacological potential including cancer treatment (Bar‐Sela, Epelbaum, & Schaffer, ; Zhu, Warin, Soroka, Chen, & Sang, ).…”

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“…Cancer-related functions of PCBP2, TIA-1, HuR/ELAVL1, SERBP1, YTHDC2, YTHDF2 (Mapofthecell database) were described above. All experimentally defined partners of eEF1Bγ picked up by Cytoscape to build molecular networks, are linked to cancer as well [2,[125][126][127][128][129][130][131][132].…”