LIM kinases are required for invasive path generation by tumor and tumor-associated stromal cells

Abstract

Leading cells require LIMK for matrix degradation and invadopodia formation during collective cell migration.

Targeting MRCK and LIMK kinases for cancer therapy

“…1) (5). Results from clinical and basic studies indicate that LIM kinases are important factors in cancer cell invasion and metastasis (5,12), while in vivo studies indicated that interfering with LIMK function inhibited metastasis (13,14). These reports are consistent with the hypothesis that LIMK inhibition would effectively reduce cancer cell invasion and metastasis.…”

“…Although the use of LIMK inhibitors to block cancer cell invasiveness and metastasis was one initial potential application (12), several recent reports indicate that they may be useful for treating primary tumors (21,25). In addition, the observation that LIMK inhibition sensitizes tumor cells to genotoxic chemotherapeutic agents (15) suggests that LIMK inhibitors might be effective in combination therapies.…”

Trailblazing LIM kinases take the lead in collective tumor cell invasion

“…6 Using threedimensional invasion assays we found that LIMK inhibition by either method resulted in significantly decreased invasion. 7 Interestingly, although many reports in the literature have implicated a specific role for either LIMK1 or LIMK2 in various processes, [8][9][10][11] we found that the selective knockdown of either protein alone had only small effects that were additive when both were targeted or inhibited simultaneously. Similar results were reported for individual versus combined knockdown of LIMK1 and LIMK2 in a zebrafish xenograft model of pancreatic cancer metastasis.…”

“…23 Given that inhibiting LIMK also reduced matrix degradation, we also wondered whether proteolysis actually facilitated contraction. When MT1-MMP, which is the major matrix metalloprotease in CAFs, 7 was knocked down there was a significant inhibition in collagen contraction. Therefore, we concluded one way LIMK activity contributes to matrix remodeling is to facilitate the proteolysis of cross-linked matrix proteins that would otherwise be too rigid for contraction to occur.…”

Discovery, Development, and SAR of Aminothiazoles as LIMK Inhibitors with Cellular Anti-Invasive Properties

“…LIM kinases are therefore centrally positioned regulators of actin cytoskeletal dynamics and also play important roles in microtubule organization. 2,3 LIMK1 has been reported to play a key regulatory role in tumour cell invasion and the level of LIMK1 is increased in invasive breast, 4 prostate, 5 and pancreatic 6 cancer cell lines in comparison with less invasive cells. Overexpression of LIMK1 in MCF-7 and in MDA MB-231 human breast cancer cell lines increased their motility, while inhibition of LIMK1 activity in MDA MB-231 cells by expression of a dominant negative LIMK1 resulted in decreased motility and formation of osteolytic bone lesions in an animal model of tumour invasion.…”