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Carcinoma matrix controls resistance to cisplatin through talin regulation of NF-kB
Karen E Eberle1, Hope A Sansing, Peter Szaniszlo
1Department of Oral and Craniofacial Biology, School of Dentistry, Louisiana State University Health Sciences Center-New Orleans, New Orleans, Louisiana, United States of America.
Abstract:
Extracellular matrix factors within the tumor microenvironment that control resistance to chemotherapeutics are poorly understood. This study focused on understanding matrix adhesion pathways that control the oral carcinoma response to cisplatin. Our studies revealed that adhesion of HN12 and JHU012 oral carcinomas to carcinoma matrix supported tumor cell proliferation in response to treatment with cisplatin. Proliferation in response to 30 µM cisplatin was not observed in HN12 cells adherent to other purified extracellular matrices such as Matrigel, collagen I, fibronectin or laminin I. Integrin β₁ was important for adhesion to carcinoma matrix to trigger proliferation after treatment with cisplatin. Disruption of talin expression in HN12 cells adherent to carcinoma matrix increased cisplatin induced proliferation. Pharmacological inhibitors were used to determine signaling events required for talin deficiency to regulate cisplatin induced proliferation. Pharmacological inhibition of NF-kB reduced proliferation of talin-deficient HN12 cells treated with 30 µM cisplatin. Nuclear NF-kB activity was assayed in HN12 cells using a luciferase reporter of NF-kB transcriptional activity. Nuclear NF-kB activity was similar in HN12 cells adherent to carcinoma matrix and collagen I when treated with vehicle DMSO. Following treatment with 30 µM cisplatin, NF-kB activity is maintained in cells adherent to carcinoma matrix whereas NF-kB activity is reduced in collagen I adherent cells. Expression of talin was sufficient to trigger proliferation of HN12 cells adherent to collagen I following treatment with 1 and 30 µM cisplatin. Talin overexpression was sufficient to trigger NF-kB activity following treatment with cisplatin in carcinoma matrix adherent HN12 cells in a process disrupted by FAK siRNA. Thus, adhesions within the carcinoma matrix create a matrix environment in which exposure to cisplatin induces proliferation through the function of integrin β₁, talin and FAK pathways that regulate NF-kB nuclear activity.
Insights
Tumor matrix adhesion promotes oral cancer cell proliferation during cisplatin treatment. Integrin β₁, talin, and FAK pathways regulate nuclear NF-kB activity, influencing chemotherapy resistance.
Area of Science:
- Molecular oncology
- Tumor microenvironment research
- Cancer cell adhesion mechanisms
Background:
- Extracellular matrix (ECM) factors in the tumor microenvironment significantly influence chemotherapy resistance, but their precise roles remain unclear.
- Understanding how matrix adhesion pathways impact oral carcinoma response to cisplatin is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To elucidate the role of matrix adhesion pathways in controlling oral carcinoma cell response to cisplatin treatment.
- To identify key molecular players, including integrins and signaling molecules, involved in cisplatin resistance mediated by the tumor microenvironment.
Main Methods:
- Cultured HN12 and JHU012 oral carcinoma cells on various extracellular matrices, including native carcinoma matrix and purified matrices (Matrigel, collagen I, fibronectin, laminin I).
- Assessed tumor cell proliferation in response to cisplatin treatment (30 µM).
- Investigated the role of integrin β₁, talin, and focal adhesion kinase (FAK) using gene disruption (siRNA) and pharmacological inhibitors.
- Measured nuclear NF-kB activity using a luciferase reporter assay.
Main Results:
- Adhesion to carcinoma matrix, but not other purified matrices, supported oral carcinoma cell proliferation upon cisplatin exposure.
- Integrin β₁ and talin were critical for this matrix-dependent proliferation; talin disruption enhanced cisplatin-induced proliferation.
- Talin deficiency-mediated proliferation was dependent on NF-kB signaling, with maintained NF-kB activity in carcinoma matrix-adherent cells post-cisplatin treatment.
- Talin expression restored cisplatin-induced proliferation and NF-kB activity in cells on collagen I, a process modulated by FAK.
Conclusions:
- Carcinoma matrix adhesions create a pro-proliferative environment for oral cancer cells under cisplatin stress.
- The integrin β₁-talin-FAK-NF-kB axis is a key pathway mediating chemotherapy resistance in oral carcinoma.
- Targeting these matrix-adhesion-mediated signaling pathways may offer novel strategies to overcome cisplatin resistance in oral cancers.
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