Elevated p21-Activated Kinase 2 Activity Results in Anchorage-Independent Growth and Resistance to Anticancer Drug–Induced Cell Death

Abstract

p21-activated kinase 2 (PAK-2) seems to be a regulatory switch between cell survival and cell death signaling. We have shown previously that activation of full-length PAK-2 by Rac or Cdc42 stimulates cell survival, whereas caspase activation of PAK-2 to the proapoptotic PAK-2p34 fragment is involved in the cell death response. In this study, we present a role of elevated activity of full-length PAK-2 in anchorage-independent growth and resistance to anticancer drug-induced apoptosis of cancer cells. Hs578T human breast cancer cells that have low levels of PAK-2 activity were more sensitive to anticancer drug-induced apoptosis and showed higher levels of caspase activation of PAK-2 than MDA-MB435 and MCF-7 human breast cancer cells that have high levels of PAK-2 activity. To examine the role of elevated PAK-2 activity in breast cancer, we have introduced a conditionally active PAK-2 into Hs578T human breast cells. Conditional activation of PAK-2 causes loss of contact inhibition and anchorage-independent growth of Hs578T cells. Furthermore, conditional activation of PAK-2 suppresses activation of caspase 3, caspase activation of PAK-2, and apoptosis of Hs578T cells in response to the anticancer drug cisplatin. Our data suggest a novel mechanism by which full-length PAK-2 activity controls the apoptotic response by regulating levels of activated caspase 3 and thereby its own cleavage to the proapoptotic PAK-2p34 fragment. As a result, elevated PAK-2 activity interrupts the apoptotic response and thereby causes anchorage-independent survival and growth and resistance to anticancer drug-induced apoptosis.

Phosphorylation of Caspase-7 by p21-activated Protein Kinase (PAK) 2 Inhibits Chemotherapeutic Drug-induced Apoptosis of Breast Cancer Cell Lines

“…Full-length PAK2 can induce cell survival, and caspase-mediated cleaved PAK2p34 can induce apoptosis. A recent study indicates that full-length PAK2 can negatively regulate caspase-3-activated proteolytic PAK2p34, activation of caspase-3, and apoptotic histone H2B phosphorylation (42). This suggests that full-length PAK2 can negatively regulate proteolytic PAK2p34 to promote cell proliferation.…”

Gastrointestinal hormones/neurotransmitters and growth factors can activate P21 activated kinase 2 in pancreatic acinar cells by novel mechanisms

“…In regards to the pancreas, except in the case of islet function[16,24,35], there are no studies examining the presence of PAKs in exocrine tissues and their activation or signaling has not been investigated. However, previous studies report CCK activates the small GTP binding proteins, Rho and Rac1, which are one of the main stimulants of PAKs in other tissues[13].…”

“…Group-I-PAKs (PAK 1–3) are the most extensively studied and play an important role in signaling for many cellular processes, such as regulation of cell survival, apoptosis, cell motility, tumorigenesis, protein synthesis, glucose homeostasis, secretion and cellular proliferation [1–5,7–14]. The Group-I-PAKs normal tissue expression varies greatly between the three isoforms [15,16]. PAK2 is expressed in a wide variety of different tissues and can be thought of as ubiquitously expressed.…”

“…Pancreatic acinar cells possess receptors for a large number of GI hormones/neurotransmitters and growth factors and are an excellent model to study their cellular basis of action, because the agents also alter cellular function activating numerous cellular signaling cascades [32–34]. At present it is unclear if any Group-I-PAKs occur in pancreatic acinar cells, although it is known at least 2 types (PAK1, 3) occur in pancreatic islets [16,35,36]. It is also unknown whether activation of any of the GI hormones/neurotransmitters receptors or GI growth factors receptors in these cells activate acinar cell PAKs, or if present, any information on the cellular signaling mechanisms involved.…”

PAK signalling during the development and progression of cancer

“…The resulting proteolytic fragment, PAK2-p34, containing the protein kinase domain, induces nuclear blebbing and reduced protein synthesis, the latter mediated by phosphorylation of MAPK signal-integrating kinase 1 (MNK1) 49 . Interestingly, conditional activation of PAK2 in Hs578T human breast carcinoma cells suppresses activation of caspase-3, generation of PAK2-p34, and apoptosis in response to the anticancer drug cisplatin 50 . These data suggest a feedback process in which PAK2 promotes survival in part by suppressing its own cleavage to a pro-apoptotic fragment.…”