LIM-kinase 2, a regulator of actin dynamics, is involved in mitotic spindle integrity and sensitivity to microtubule-destabilizing drugs

Abstract

LIM-kinase 2 (LIMK2) belongs to the LIMK family of proteins, which comprises LIMK1 and LIMK2. Both proteins regulate actin polymerization through phosphorylation and inactivation of the actin depolymerizing factor cofilin. In this study, we show that the level of LIMK2 protein is increased in neuroblastoma, BE(2)-C cells, selected for resistance to microtubule-destabilizing agents, vincristine and colchicine. However, the level of phosphorylated LIMK1 and LIMK2 was similar in the resistant and parental BE(2)-C cells. In contrast, the level of phospho-cofilin was greatly increased in the drugresistant cells. Downregulation of LIMK2 expression increases sensitivity of neuroblastoma SH-EP cells to vincristine and vinblastine but not to microtubule-stabilizing agents, while it's overexpression increased its resistance to vincristine. Its vincristine-induced mitotic arrest was moderately inhibited in the LIMK2 knockdown cells, suggesting that the increased drug sensitivity is through an alternative mechanism other then mitotic arrest and apoptosis. Moreover, downregulation of LIMK2 expression induces formation of abnormal mitotic spindles, an effect enhanced in the presence of microtubule-destabilizing agents. LIMK2 is important for normal mitotic spindle formation and altered LIMK2 expression mediates sensitivity to microtubule destabilizing agents. These findings suggest that inhibition of LIMK2 activity may be used for the treatment of tumors resistant to microtubuledestabilizing drugs.

Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation

“…An inference from this study is that because LIMK2 levels are decreased in a sizeable proportion of CRC patients, these cancers might be more effectively treated with some chemotherapeutics because knocking down and/or inhibiting LIMK2 sensitises cancer cells to DNA damaging agents,17 Aurora A inhibitors,54 Ras inhibition55 and microtubule-destabilising drugs such as vincristine and vinblastine 56. Therefore, knowledge of LIMK2 expression levels in CRC may have utility in patient stratification for the development of personalised therapies.…”

TPPP acts downstream of RhoA-ROCK-LIMK2 to regulate astral microtubule organization and spindle orientation

“…Additional evidence comes from the observations that LIMK1 is localized to the centrosomes and LIMK2 to the mitotic spindles (Sumi et al, 2006). Knocking down LIMK2 also increases the number of abnormal spindles in cells treated with microtubule-destabilizing drugs (Po'uha et al, 2010). Interestingly, it has also been reported that ROCK phosphorylates LIMK2 downstream of RhoA activation (Sumi et al, 2001), but not LIMK1, which is phosphorylated by the PAK kinases (Edwards et al, 1999).…”

Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy

“…In addition, knockdown of LIMK2 in cell lines results in significantly reduced neurite bearing cell count, neurite length, and cone extension growth rate 29. Furthermore, LIMK2 expression has been implicated in sensitivity to the microtubule binding agents vincristine and vinblastine in a neuroblastoma cell line 30. With respect to other genes at this locus, PIK3IP is a negative regulator of PI3K and PLA2G3 is involved in oxidative stress and is associated with Alzheimer's disease.…”