Kindlin-2 Regulates Integrin Function And Sensitivity To Docetaxel In Prostate Cancer Cells

Over the past decade, many lines of evidence have emerged to implicate the three members of the kindlin family of FERM domain proteins as important regulators of integrin adhesion receptors. Specifically, kindlins appear to cooperate with talin to be essential regulators of the ligand binding function of integrins and thereby enhance the adhesive and migratory responses of cells. Kindlin-2 (FERMT2) is the most broadly distributed of the kindlins. To explore the relationship between integrin activation and kindlin-2, prostate cancer cell lines were screened and LNCaP prostate cancer cells were found to express relatively low levels of kindlin-2 and endogenous levels of beta-1 integrin on their surface. A portion of this integrin was expressed in an activated state as detected with an activation specific antibody, HUTS-4. These cells were transfected with vectors for kindlin-2, with or without talin-head domain, a combination that leads to activation of β3 integrins in model cells. Transfections with kindlin-2 suppressed β1 integrin activation on the surface of the LNCaP cells. This inhibitory effect was abolished by mutation of kindlin-2 that prevented its binding to integrin cytoplasmic tail. This inhibitory response to kindlin-2 on β1 integrin was in stark contract to the effects of kindlin-2 plus talin-head expression on β3 function, where co-expression of the same constructs enhanced integrin activation. A mutation in kindlin-2, deletion of its last 15 amino acids, that blocks activation of β3 integrins without preventing its binding to the integrin, also prevents its inhibition of β1 function. We next looked at the effects of kindlin-2 on docetaxel induced apoptosis as monitored with Annexin V staining and cell death as monitored by propidium iodide staining (both by flow cytometry). Compared to LNCaP cells expressing EGFP alone, cells overexpressing EGFP-kindlin-2 were protected against apoptosis and cell death. This effect was dependent upon binding of kindlin-2 to the cytoplasmic tail of integrins. Hence, the capacity of kindlin-2 to influence integrin function depends upon the integrin subfamily and can range from activation to suppression of function. Kindlin-2, which is often overexpressed in transformed cells, may desensitize cells towards chemotherapeutic agents. Citation Format: Edward F. Plow, Mitali Das, Jamila Hirbawi, Khalid Sossey-Alaoui. Kindlin-2 regulates integrin function and sensitivity to docetaxel in prostate cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 405. doi:10.1158/1538-7445.AM2015-405