Combined inhibition of PAK7, MAP3K7 and CK2α kinases inhibits the growth of MiaPaCa2 pancreatic cancer cell xenografts

Abstract

A panel of kinases whose inhibition increased apoptosis of pancreatic adenocarcinoma cells in vitro was recently established. The aim of this work was to observe in a mouse xenograft model whether inhibition of these kinases would alter pancreatic tumor growth. Rate of apoptosis, caspase-3 activity and cell viability were assessed in two pancreatic cancer cell lines, MiaPaCa2 and BxPC3, after inhibiting selected kinases by transfection of specific siRNAs. For in vivo experiments, MiaPaCa2 cells were injected into the pancreas of nude mice, where they formed tumors. Inhibition of kinases was obtained by repeated intraperitoneal (i.p.) injections of modified O-Methyl (OMe) siRNAs specific for the selected kinases. Tumor volumes were assessed after 21 days. Among selected kinases, PAK7, MAP3K7 and CK2a were those whose inhibition increased apoptosis the most in vitro. Simultaneous inhibition of two of them increased apoptosis up to five times. Moreover, inhibiting these kinases had little effect on 10 non-pancreatic cell lines, suggesting pancreatic specificity. In vivo, OMe-siRNAs induced significant but incomplete inhibition of kinase expression (45-75%). Nevertheless, such inhibition resulted in a twofold increase in caspase-3 activity in tumors and a strong reduction in tumor volume (about 75%). In vivo inhibition by OMe-siRNAs of three survival kinases apparently specific for pancreatic cancer cells, PAK7, MAP3K7 and CK2a, decreases significantly the growth of xenografted MiaPaCa2 cells. This strategy is therefore of potential clinical interest.

High-level expression of P21-Cdc/Rac-activated kinase 7 is closely related to metastatic potential and poor prognosis of colon carcinoma

“…However, the overexpression of PAK7 increases the migration and invasion of colon cancer cells in vitro . Our findings are consistent with other recent studies, which have identified an important role of PAK7 in tumorigenesis and metastasis of breast, pancreatic, and gastric cancer cells [21, 27, 28]. …”

ERK2 is essential for the growth of human epithelioid malignant mesotheliomas

“…As shown in Table S1, mRNA levels of a number of genes were significantly increased or decreased in microarray analyses after silencing of either ERK1 or ERK2 , and these patterns were confirmed in 13 selected genes using qRT-PCR (Figure 5). Several of these genes, including PAK7 or other members of this serine/threonine protein kinase family can directly activate MEK1 and inhibit cell transformation by preventing Ras-induced activation of ERKs 27, 28. Others such as BMP5 are activated via synergistic activation of Smad and p38 kinases and are differentially regulated during limb and tumor development 29.…”

Neoadjuvant therapy is associated with improved survival in resectable pancreatic adenocarcinoma

“…5). Several of these genes including PAK7 or other members of this serine/threonine protein kinase family can directly activate MEK1 and inhibit cell transformation by preventing Ras‐induced activation of ERKs 27, 28. Others such as BMP5 are activated via synergistic activation of Smad and p38 kinases and are differentially regulated during limb and tumor development 29.…”