Inhibition of group 1 p21‐activated kinases suppresses pancreatic stellate cell activation and increases survival of mice with pancreatic cancer

Abstract

Pancreatic cancer remains one of the most lethal of all solid tumors. Pancreatic stellate cells (PSCs) are primarily responsible for the fibrosis that constitutes the stroma and p21-activated kinase 1 (PAK1) may have a role in signalling pathways involving PSCs. This study aimed to examine the role of PAK1 in PSCs and in the interaction of PSCs with pancreatic cancer cells. Human PSCs were isolated using the modified outgrowth method. The effect of inhibiting PAK1 with group 1 PAK inhibitor, FRAX597, on cell proliferation and apoptosis in vitro was measured by thymidine incorporation and annexin V assays, respectively. The effect of depleting host PAK1 on the survival of mice with pancreatic Pan02 cell tumors was evaluated using PAK1 knockout (KO) mice. PAK1 was expressed in isolated PSCs. FRAX597 reduced the activation of PSCs, inhibited PSC proliferation, and increased PSC apoptosis at least in partial by inhibiting PAK1 activity. The decreased expression and activity of PAK1 in PAK1 KO mice tumors was associated with an increased mouse survival. These results implicate PAK1 as a regulator of PSC activation, proliferation and apoptosis. Targeting stromal PAK1 could increase therapeutic response and survival of patients with pancreatic cancer.

Retracted Article: ASIC1a involves acidic microenvironment-induced activation and autophagy of pancreatic stellate cells

“…Activated PSCs play a pivotal role in the pathologic processes of pancreatic diseases, and inhibition of PSCs activation, or even the transformation of activated PSCs into quiescence PSCs, has been found to be benecial to the treatment of pancreatic cancer and pancreatitis. [18][19][20] The activated PSCs are positive for a-SMA, collagen 1, so this two molecules are oen used as the marker of PSCs activation. 21 As shown in Fig.…”

The PAK Inhibitor PF-3758309 Promotes the Inhibitory Effects of Multiple Chemotherapeutic Reagents on Patient-Derived Pancreatic Cancer Cell Lines

“…α-SMA is an established marker for PSC activation [27], and its expression is negatively correlated with PDA survival [28]. We have previously reported that inhibition of PAK1 decreased proliferation and increased apoptosis of PSCs while suppressing SMA expression in PSCs [12]. Here for the first time we have detected the expression of -SMA by both Western blot and immunofluorescent staining in cells established from xenografts isolated from pancreatic cancer patients.…”

“…Inhibition of PAK1 synergistically with gemcitabine reduced the growth of pancreatic cancer cells in vitro and in vivo [10], and activation of PAK1 contributed to gemcitabine resistance of pancreatic cancer cells [11]. Inhibition of PAK1 also suppressed PSC activation and proliferation while promoting apoptosis, and deletion of stromal PAK1 increased survival of mice with PDA [12]. PAK4 promoted PDA cell proliferation and survival by activation of the NF-κB pathway [13], and inhibition of PAK4 increased the sensitivity of PDA cells to gemcitabine [14].…”

p21-activated kinase signalling in pancreatic cancer: New insights into tumour biology and immune modulation

“…A recent study revealed the role of PAK1 in PSC modulation for the first time by showing that inhibition of PAK1 by FRAX597 (a potent group I PAK inhibitor) reduced the activation and proliferation of PSC and increased apoptosis in vitro . In an orthotopic pancreatic cancer mouse model, survival in the PAK1 knockout group was significantly increased compared to the PAK1 wildtype group, and depletion of PAK1 in the pancreatic stroma also reduced PAK1 expression and activity in the tumour[ 64 ]. Similarly, survival was prolonged in the group treated with FRAX597 plus gemcitabine in the same orthotopic pancreatic cancer model[ 59 ].…”

“…The extensive desmoplastic reaction, which is a hallmark of pancreatic cancer, is reported to result in a dense stroma, deficient vascularization and inefficient drug delivery, eventually leading to chemo-resistance[ 96 , 97 ]. As mentioned above, PAK1 is responsible for PSC activation, leading to stromal fibrosis[ 64 ] in pancreatic cancer similar to its pivotal role in liver fibrogenic pathways[ 98 ].…”