Pharmacological Inhibition of LIM Kinase Stabilizes Microtubules and Inhibits Neoplastic Growth

Abstract

The emergence of tumor resistance to conventional microtubule-targeting drugs restricts their clinical use. Using a cell-based assay that recognizes microtubule polymerization status to screen for chemicals that interact with regulators of microtubule dynamics, we identified Pyr1, a cell permeable inhibitor of LIM kinase, which is the enzyme that phosphorylates and inactivates the actin-depolymerizing factor cofilin. Pyr1 reversibly stabilized microtubules, blocked actin microfilament dynamics, inhibited cell motility in vitro and showed anticancer properties in vivo, in the absence of major side effects. Pyr1 inhibition of LIM kinase caused a microtubulestabilizing effect, which was independent of any direct effects on the actin cytoskeleton. In addition, Pyr1 retained its activity in multidrug-resistant cancer cells that were resistant to conventional microtubuletargeting agents. Our findings suggest that LIM kinase functions as a signaling node that controls both actin and microtubule dynamics. LIM kinase may therefore represent a targetable enzyme for cancer treatment.

Targeting cancer cell integrins using gold nanorods in photothermal therapy inhibits migration through affecting cytoskeletal proteins

“…Studies on the changes of cytoskeletal components could provide novel therapeutic approaches to prevent cancer cell migration and metastasis (4). The targeting of cytoskeletal components, such as actin or tubulin (6,7), or regulatory proteins, such as Rho-ROCK or LIM kinases, has been shown to inhibit the invasive and metastatic behavior of cancer cells (8,9). However, the pharmacological inhibitors of cytoskeleton have not been very effective in clinical trials due to their nonspecific targeting of cytoskeleton in normal cells, which might cause side effects, such as cardiotoxicity (4,7,10).…”

Cytoskeletal Molecules Play a Major Role in Cancer Progression

“…We and others have demonstrated that by controlling actin filamental formation through inhibition of LIMK activity; tumour growth, invasion and migration can be prevented [2,16,17].…”

“…Normal cell behavior regulated via the cytoskeletal filaments are altered in cancer. Several studies have demonstrated that alteration of cytoskeletal structures play a pivotal role in controlling cell behavior including in cancerous cells [1][2][3].…”

Targeting MRCK and LIMK kinases for cancer therapy

“…Given that LIMK inhibitors have now been developed by a number of drug discovery efforts (20)(21)(22)(23)(24), it should be possible for thorough pharmacological proof of concept experiments to be undertaken to test the hypothesis that LIM kinases are valid cancer targets. 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).…”

“…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.…”