Molecular Pathways: Targeting P21-Activated Kinase 1 Signaling in Cancer—Opportunities, Challenges, and Limitations

Abstract

The evolution of cancer cells involves deregulation of highly regulated fundamental pathways that are central to normal cellular architecture and functions. The p21-activated kinase 1 (PAK1) was initially identified as a downstream effector of the GTPases Rac and Cdc42. Subsequent studies uncovered a plethora of its new functions in growth factor and steroid receptor signaling, cytoskeleton remodeling, cell survival, oncogenic transformation, and gene transcription, largely through systematic discovery of its direct, physiologically relevant substrates. PAK1 is widely up-regulated in several human cancers including hormone-dependent cancer, and is intimately linked to tumor progression and therapeutic resistance. These exciting developments combined with the kinase-independent role of PAK1-centered phenotypic signaling in cancer cells elevated PAK1 as an attractive drug target. The structural and biochemical studies revealed the precise mechanism of PAK1 activation, offering the possibilities to develop PAK1-targeted cancer therapeutic approaches. In addition, emerging reports suggest the potential of PAK1 and its specific phosphorylated substrates as cancer prognostic markers. Here, we summarize the PAK1 molecular pathways in human cancer and discuss the current status of PAK1 targeted anti-cancer therapies.

P21 Activated Kinase-1 (Pak1) Promotes Prostate Tumor Growth and Microinvasion via Inhibition of Transforming Growth Factor β Expression and Enhanced Matrix Metalloproteinase 9 Secretion

“…We also demonstrated previously that Pak1 inhibition prevents oncogenic transformation and tumor growth in vivo through uncoupling of Akt from cRaf-ERK pathways (8). Although Pak1 has been implicated in the attainment of migratory and invasive potential by a variety of cancer cell types (25)(26), this is the least studied Pak isoform in prostate cancer, probably because the prostate is well known for its higher expression of group II Paks such as Pak4 and Pak6 compared with group I Paks such as Pak1 and Pak2. Because group II Paks are not common effectors downstream of Rac1 activation (1), we hypothesized that our previous observation of Rac1-mediated activation of prostate cancer cells (13) is mediated via utilizing a mechanism independent of Pak6.…”

p21-Activated Kinase 1 (PAK1) Can Promote ERK Activation in a Kinase-independent Manner

“…PAK1 is widely up-regulated and hyperactivated in several human cancers, such as breast cancers, neurofibromatosis, and colorectal cancers (8,10,11). Although it has been shown by several groups that PAK1 regulates ERK-dependent proliferation, the molecular details of this process are not entirely clear.…”

“…Activity-PAK1 has been reported to be hyperactivated in various cancer tissues to promote cancer cell proliferation (8). However, unexpectedly, after we transfected two colon cancer cell lines, SW480 and HT-29 as well as HeLa cells with wild type PAK1 (PAK1 WT ) or kinase-negative PAK1 (K298R; PAK1 K298R ) plasmids, we observed an increase of p-PAK1/2 (Ser-144/Ser-141) and p-ERK1/2(Thr-202/Tyr-204) by Western blot.…”

PAK1 Promotes Intestinal Tumor Initiation

“…PAK1 is a serine/threonine kinase effector of the small Rho GTPases Rac1/Cdc42 with both kinase and scaffolding activities (11). Accumulating evidence suggests that PAK1 signaling actively participates in gut homeostasis (12).…”