Balanced Tiam1-Rac1 and RhoA Drives Proliferation and Invasion of Pancreatic Cancer Cells

Abstract

Tiam1 is a rac1-specific guanine nucleotide exchange factor, and Tiam1-rac1 is involved in a number of cellular processes. Rac1 and RhoA act as molecular switches that cycle between GTP-and GDP-bound states to balance the activities of rac1 and RhoA. The downregulation of rac1 activity leads to upregulation of RhoA activity, which promotes invasion and migration of pancreatic cancers cells. At present, however, the role of Tiam1-rac1 and RhoA in pancreatic cancers is not fully understood. We found that Tiam1 was upregulated in pancreatic cancers and was significantly expressed in tumors without lymph node involvement or distant metastasis compared with cancers where there was involvement. Although Tiam1-rac1 signaling promoted pancreatic cancer cell proliferation and tumor growth via the Wnt signaling pathway in vitro and in vivo, inhibiting Tiam1-rac1 signaling did not prolong the overall survival time in vivo. This provided evidence that there was a balance between rac1 and RhoA activities in pancreatic cancers. Furthermore, only the combined inhibition of Tiam1-rac1 and RhoA had a beneficial effect on the growth of pancreatic cancers in vivo. Taken together, these results suggest that the progression of pancreatic tumors is partially controlled by the balance between Tiam1-rac1 and RhoA.

Par3 regulates invasion of pancreatic cancer cells via interaction with Tiam1

“…Silencing of Tiam1 or Par3 did not affect expression of one another, or Par6, or aPKC, but did disturb Par3-Tiam1 interaction, thus disturbing tight junction assembly. We found Tiam1 to play an important role in pancreatic cancer [23].…”

Tiam1/Rac1 signals contribute to the proliferation and chemoresistance, but not motility, of chronic lymphocytic leukemia cells

“…[36][37][38][39] A recent report suggests that a balance of Tiam1-Rac1-and RhoA-mediated signals is important for pancreatic cancer cell proliferation and invasion, respectively. 40 Knocking down Tiam1 in the tumor cells increased their migratory capacity, accompanied by increased RhoA activity. 40 Because Tiam1/ Rac signals have previously been considered imperative for lamellipodium formation, chemokine-induced motility, and homing of multiple other nontransformed cell types, 41 this observation points to a differential usage of Tiam1/Rac in cancer cells.…”

Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer

“…The inhibition of cell proliferation could be the consequence of, a) angiogenesis inhibition because angiogenesis is absolutely required for tumor growth; b) consequence of the inhibition of Rac1 which is also involved in cell proliferation (43) or c) a consequence of ZA treatment, we previously showed that ZA not only has anti-angiogenic activity but also anti-proliferative and pro-apoptotic effects (19). In this study, we observed that ZA induces apoptosis in OVCAR-5 in vivo model (Supplementary Fig S1A) and in HeyA8-MDR both in vitro and in vivo (Supplementary Fig S1B–D).…”