Group I p21-activated kinases (PAKs) promote tumor cell proliferation and survival through the AKT1 and Raf-MAPK pathways

Our plain-English summary of Group I p21-activated kinases (PAKs) promote tumor cell proliferation and survival through the AKT1 and Raf-MAPK pathways, by C.W. Menges, E. Sementino, J. Talarchek, et al (Molecular Cancer Research, 2012).

The study

• Authors: C.W. Menges, E. Sementino, J. Talarchek, J. Xu, J. Chernoff, J.R. Peterson, J.R. Testa
• Journal: Molecular Cancer Research
• Published: 2012;10(9):1178-88
• Cited by: 38 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Group I p21-activated kinases (PAK) are important effectors of the small GTPases Rac and Cdc42, which regulate cell motility/migration, survival, proliferation, and gene transcription. Hyperactivation of these kinases have been reported in many tumor types, making PAKs attractive targets for therapeutic intervention. PAKs are activated by growth factor-mediated signaling and are negatively regulated by the tumor suppressor neurofibromatosis type 2 (NF2)/Merlin. Thus, tumors characterized by NF2 inactivation would be expected to show hyperactivated PAK signaling. On the basis of this rationale, we evaluated the status of PAK signaling in malignant mesothelioma, an aggressive neoplasm that is resistant to current therapies and shows frequent inactivation of NF2. We show that group I PAKs are activated in most mesotheliomas and mesothelioma cell lines and that genetic or pharmacologic inhibition of PAKs is sufficient to inhibit mesothelioma cell proliferation and survival. We also identify downstream effectors and signaling pathways that may contribute mechanistically to PAK-related tumorigenesis. Specifically, we show that inhibition of PAK results in attenuation of AKT and Raf-MAPK signaling and decreased tumor cell viability. Collectively, these data suggest that pharmacologic inhibition of group I PAKs may have therapeutic efficacy in tumors characterized by PAK activation.

In plain English

This laboratory study examined whether group I p21-activated kinases (PAKs), a family of enzymes, are switched on in malignant mesothelioma, and whether blocking them harms mesothelioma cells. The authors stained archival human tumor samples and asbestos-induced mouse mesotheliomas, and tested human and mouse mesothelioma cell lines. All 15 human pleural mesothelioma specimens stained more strongly for active PAK than normal pleural lining. PAK activation was seen in about 80% of the cell lines tested that had lost NF2. Blocking PAKs genetically reduced cell viability, growth and colony formation. An experimental PAK-blocking drug, IPA-3, reduced cell viability in a dose-dependent manner. IPA-3 also increased signs of cell death. Blocking PAKs lowered activity in two growth-signaling pathways, AKT and MAPK. Switching on AKT1 or Raf1 restored cell growth in colony assays in two cell lines. The authors concluded that drugs inhibiting group I PAKs may have therapeutic value in tumors with PAK activation. The work used cells and tissue samples only, and no patients were treated.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study of human and mouse mesothelioma tissue samples and cell lines (staining, gene knockdown and drug experiments); no patients were treated
• Who was studied: Archival human pleural mesothelioma specimens (15 on a tissue microarray), asbestos-induced mesotheliomas from wild-type and Nf2+/- mice, and human and mouse mesothelioma cell lines (experiments focused on ME12, Meso 22 and Meso 17), from Fox Chase Cancer Center, Philadelphia. Dates not stated.
• Exposure: Blocking group I PAKs by genetic means (an inhibitory PAK1 fragment, PID, or shRNA knockdown of PAK1 or PAK2) or with the experimental drug IPA-3. Asbestos appears only as the cause of the mouse tumors studied.
• Main results:
  • All 15 human pleural mesothelioma specimens stained more strongly for active PAK than normal pleural lining.
  • PAK phosphorylation (activation) was observed in about 80% of the human and mouse mesothelioma cell lines tested that had lost NF2 expression. The total number of cell lines is not given in the text.
  • In ME12 and Meso 22 cells, expressing the inhibitory PID fragment reduced cell viability by at least 2-fold.
  • No colonies formed in any of the three cell lines stably expressing PID, while control cells formed colonies.
  • Knocking down PAK1 had a modest effect on proliferation, except with one shRNA in Meso 22 cells. Knocking down PAK2 consistently stopped proliferation in ME12 cells, but only one PAK2 shRNA clearly changed Meso 22 proliferation.
  • IPA-3 given for 72 hours reduced mesothelioma cell viability in a dose-dependent manner. The concentration that reduced viability by half (IC50) was approximately 25 µM.
  • IPA-3-treated ME12 and Meso 22 cells showed a significant increase in DNA fragmentation, a marker of cell death, compared with control cells.
  • IPA-3 treatment reduced phosphorylation (activity) of AKT and ERK1/2. The authors described the effect on these pathways as modest but reproducible.
  • Constitutively active AKT1 and Raf1 each restored cell viability in colony assays despite PAK inhibition by PID, in two mesothelioma cell lines.
• The authors' conclusion: The authors concluded that their data suggest drugs inhibiting group I PAKs may have therapeutic efficacy in tumors characterized by PAK activation.
• Limitations the authors state:
  • Not all NF2-deficient cell lines showed strong PAK activation, suggesting other pathways may control PAK activity.
  • Transfection efficiency is generally low in mesothelioma cell lines, which limited the short-term PID experiments.
  • The genetic methods used (PID or shRNA expression) are not feasible as cancer therapy.
  • It is not clear which downstream targets of PAKs are critical for mesothelioma cell proliferation and survival.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Merlin, Malignant Mesothelioma, Neoplasm, Mesothelioma, Tumorigenesis.

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