Abrogation of PIK3CA or PIK3R1 reduces proliferation, migration, and invasion in glioblastoma multiforme cells

Abstract

Glioblastoma multiforme (GBM) is a highly invasive and deadly brain tumor. Tumor cell invasion makes complete surgical resection impossible and reduces the efficacy of other therapies. Genome-wide analyses of mutations, copy-number changes, and expression patterns have provided new insights into genetic abnormalities common in GBM. We analyzed published data and identified the invasion and motility pathways most frequently altered in GBM. These were most notably the focal adhesion and integrin signaling, and extracellular matrix interactions pathways. We mapped alterations in each of these pathways and found that they included the catalytic PIK3CA and regulatory PIK3R1 subunit genes of the class IA PI3K. Knockdown of either of these genes separately in GBM cell lines by lentiviral-mediated shRNA expression resulted in decreased proliferation, migration, and invasion in all lines tested. FAK activity was reduced by knockdown of either PIK3CA or PIK3R1, and MMP2 levels were reduced by knockdown of PIK3R1. We conclude that PIK3R1, like PIK3CA, is a potential therapeutic target in GBM and that it also influences tumor cell growth and motility.

Alternatively spliced protein arginine methyltransferase 1 isoform PRMT1v2 promotes the survival and invasiveness of breast cancer cells

“…These include the previous observation that PRMT1 triggers methylation-mediated association of ERα with PI3-kinase, Src and FAK complex, 19 all of which regulate cell migration and invasion. [69][70][71][72][73] Furthermore, it has been shown that mutation of p53 is involved in the regulation of cell migration and invasion, increasing the metastatic potential of cancer cells. 74,75 While PRMT1 was previously shown to participate in p53-dependent transcriptional activation, 47 it remains unknown whether this may be linked with the mechanisms through which PRMT1v2 promotes breast cancer cell invasion.…”

GSK3β regulates Bcl2L12 and Bcl2L12A anti-apoptosis signaling in glioblastoma and is inhibited by LiCl

“…39 The abrogation of PIK3CA or PIK3R1 also reduces proliferation, migration and invasion, since these two genes are frequently found to be mutated and overexpressed in GBM. 40 NFκB is also viewed as an important therapeutic target of GBM, which implicates IKKβ inhibitors in interfering with NFκB activation in order to prohibit the limitless replicative potential, tissue invasion interrelationships among GSK3b, BCL2L12 and BCL2L12A in glioblastoma, as shown in Figure 6. Our present results indicate that overexpression of BCL2L12 and BCL2L12A in U87MG leads to STS resistance.…”

Targeting Therapeutic Liabilities Engendered by PIK3R1 Mutations for Cancer Treatment

“…One plausible underlying mechanism could be decrease in the amount of p110-unbound p85α, which is tumor suppressive as described earlier. However, it is important to note that in vitro knockdown of PIK3R1 resulted in decreased proliferation, migration and invasion in glioblastoma multiforme cells [87], suggesting that increased or decreased p85α levels could have similar effects on tumor progression depending on the context.…”