Autotaxin Promotes Cancer Invasion via the Lysophosphatidic Acid Receptor 4: Participation of the Cyclic AMP/EPAC/Rac1 Signaling Pathway in Invadopodia Formation

Abstract

The ability of cancer cells to invade and metastasize is the major cause of death in cancer patients. Autotaxin (ATX) is a secreted lysophospholipase whose level of expression within tumors correlates strongly with their aggressiveness and invasiveness. ATX is the major enzyme involved in the production of lysophosphatidic acid (LPA), a phospholipid that is known to act mostly through its three first characterized receptors (LPA 1 , LPA 2 , and LPA 3 ). Tumor cell invasion across tissue boundaries and metastasis are dependent on the capacity of invasive cancer cells to breach the basement membrane. This process can be initiated by the formation of the actin-rich cell protrusions, invadopodia. In this study, we show that ATX is implicated in the formation of invadopodia in various cancer cells types and this effect is dependent on the production of LPA. We further provide evidence that LPA 4 signaling in fibrosarcoma cells regulates invadopodia formation downstream of ATX, a process mediated through the activation of EPAC by cyclic AMP and subsequent Rac1 activation. Results using LPA 4 shRNA support the requirement of the LPA 4 receptor for cell invasion and in vivo metastasis formation. This work presents evidence that blocking the LPA receptor, LPA 4 , in fibrosarcoma cells could provide an additional tool to improve the efficacy of treatment of metastasis in patients. Because LPA receptors and ATX are currently being targeted in preclinical trials, the current findings should stimulate future studies to evaluate the expression pattern and clinical outcome of LPA 4 , together with other LPA receptors, in various cancer patients. Cancer Res; 70(11); 4634-43. ©2010 AACR.

A RhoG-mediated signaling pathway that modulates invadopodia dynamics in breast cancer cells

“…In that study, silencing the expression of Rac1 or Trio was also shown to promote an increase in invadopodia lifetime, without affecting invadopodia numbers (Moshfegh et al, 2014). Even though our results contradict those of Moshfegh and colleagues (2014), they are in agreement with several reports which show Rac1 is required for invadopodia and podosome formation in different cell lines (Furmaniak-Kazmierczak et al, 2007;Harper et al, 2010;Lin et al, 2014;Nascimento et al, 2011;Pignatelli et al, 2012;Wheeler et al, 2006). Moreover, our results show that silencing SGEF or RhoG affects both invadopodia numbers and lifetime, whereas silencing Trio has no significant effect on the number of cells that form invadopodia.…”

516: Role of LPAR3, PKC and EGFR in LPA-induced cell migration in oral squamous carcinoma cells

“…For the non-EDG LPA-receptors, LPAR4-6, information on their role in cancer is very limited and few studies exist. LPAR4 has shown both antimigratory [54,55] and proinvasive effects [56]. LPAR5 inhibited migration [29], and LPAR6 (synonymous to P2Y5) was thought to be procancerous [57].…”

Autotaxin – A Target for the Treatment of Drug-Resistant Ovarian Cancer?

“…Autotaxin and LPA promote the expression of the extracellular matrix protein osteopontin which promotes migration (Zhang et al 2011). Autotaxin activates the small G-proteins cdc42 and Rac (Jung et al 2002;Hoelzinger et al 2008;Harper et al 2010) and focal adhesion kinase (Jung et al 2002), proteins which are key regulators of cell motility. More direct evidence comes from the observation that knockdown of autotaxin inhibits cell migration in several cancer types Gaetano et al 2009;Harper et al 2010) and over-expression of autotaxin increases motility Harper et al 2010).…”

“…Autotaxin activates the small G-proteins cdc42 and Rac (Jung et al 2002;Hoelzinger et al 2008;Harper et al 2010) and focal adhesion kinase (Jung et al 2002), proteins which are key regulators of cell motility. More direct evidence comes from the observation that knockdown of autotaxin inhibits cell migration in several cancer types Gaetano et al 2009;Harper et al 2010) and over-expression of autotaxin increases motility Harper et al 2010). Autotaxin regulates the formation of invadopodia (Harper et al 2010) and induces the expression of uPA ) and MMP3 (Haga et al 2009).…”

“…More direct evidence comes from the observation that knockdown of autotaxin inhibits cell migration in several cancer types Gaetano et al 2009;Harper et al 2010) and over-expression of autotaxin increases motility Harper et al 2010). Autotaxin regulates the formation of invadopodia (Harper et al 2010) and induces the expression of uPA ) and MMP3 (Haga et al 2009). Correspondingly, knockdown of autotaxin inhibits invasion (Hoelzinger et al 2008) while over-expression promotes invasion (Nam et al 2000;Yang et al 2002).…”