Apoptosis in cancer cells is induced by alternative splicing of hnRNPA2/B1 through splicing of Bcl-x, a mechanism that can be stimulated by an extract of the South African medicinal plant, Cotyledon orbiculata
Loading...
Date
Authors
Makhafola, Tshepiso Jan
Mbele, Mzwandile
Yacqub-Usman, Kiren
Hendren, Amy
Haigh, Daisy Belle
Blackley, Zoe
Meyer, Mervin
Mongan, Nigel Patrick
Bates, David Owen
Dlamini, Zodwa
Journal Title
Journal ISSN
Volume Title
Publisher
Frontiers Media
Abstract
Alternative splicing is deregulated in cancer and alternatively spliced products can
be linked to cancer hallmarks. Targeting alternative splicing could offer novel effective
cancer treatments. We investigated the effects of the crude extract of a South African
medicinal plant, Cotyledon orbiculata, on cell survival of colon (HCT116) and esophageal
(OE33 and KYSE70) cancer cell lines. Using RNASeq, we discovered that the extract
interfered with mRNA regulatory pathways. The extract caused hnRNPA2B1 to splice
from the hnRNPB1 to the hnRNPA2 isoform, resulting in a switch in the BCL2L1 gene
from Bcl-xL to Bcl-xS causing activation of caspase-3-cleavage and apoptosis. Similar
splicing effects were induced by the known anti-cancer splicing modulator pladienolide
B. Knockdown of hnRNPB1 using siRNA resulted in decreased cell viability and increased
caspase-3-cleavage, and over-expression of hnRNPB1 prevented the effect of C.
orbiculata extract on apoptosis and cell survival. The effect of the hnRNPA2/B1 splicing
switch by the C. orbiculata extract increased hnRNPA2B1 binding to Bcl-xl/s, BCL2,
MDM2, cMYC, CD44, CDK6, and cJUN mRNA. These findings suggest that apoptosis in
HCT116, OE33, and KYSE cancer cells is controlled by switched splicing of hnRNPA2B1
and BCL2L1, providing evidence that hnRNPB1 regulates apoptosis. Inhibiting this
splicing could have therapeutic potential for colon and esophageal cancers. Targeting
hnRNPA2B1 splicing in colon cancer regulates splicing of BCL2L1 to induce apoptosis.
This approach could be a useful therapeutic strategy to induce apoptosis and restrain cancer cell proliferation and tumor progression. Here, we found that the extract of
Cotyledon orbiculata, a South African medicinal plant, had an anti-proliferative effect
in cancer cells, mediated by apoptosis induced by alternative splicing of hnRNPA2B1
and BCL2L1.
Description
Keywords
Colorectal cancer, Esophageal cancer, Cotyledon orbiculata, Alternative splicing, Crude extract, South African medicinal plant, Cell survival, Colon cancer cell line (HCT116), Esophageal cancer cell line (OE33), Esophageal cancer cell line (KYSE70)
Sustainable Development Goals
Citation
Makhafola TJ, Mbele M,
Yacqub-Usman K, Hendren A,
Haigh DB, Blackley Z, Meyer M,
Mongan NP, Bates DO and Dlamini Z
(2020) Apoptosis in Cancer Cells Is
Induced by Alternative Splicing of
hnRNPA2/B1 Through Splicing of
Bcl-x, a Mechanism that Can Be
Stimulated by an Extract of the South
African Medicinal Plant, Cotyledon
orbiculata. Frontiers in Oncology 10:547392.
doi: 10.3389/fonc.2020.547392