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Investigation of L-type calcium channels as potential targets for cancer therapy

University of British Columbia

Cell surface calcium (Ca²⁺) channels permit Ca²⁺ ion influx, with Ca²⁺ taking part in cellular facets such as proliferation, survival, and activation. Greater expression of voltage-dependent Ca²⁺ (CaV) channels has been recorded for a number of different cancers. We hypothesized that the targeting of L-type CaV (CaV1) channels in leukemia and lymphoma with antibody-based biologics may act as a potential cancer therapy. Profile analysis of Ca²⁺ channels, in particular the L-type CaV channels, was performed on RNA sequencing from lymphoma and leukemia cell lines, patients with diffuse large B cell lymphoma, and patients with peripheral T cell lymphoma. Findings here included increased CaV1.3 expression in angioimmunoblastic T cell lymphoma relative to control T follicular helper cells, for example. Expression of CaV1.3 was also higher in activated B cell-like diffuse large B cell lymphoma than in germinal centre B cell-like diffuse large B cell lymphoma, with CaV1.1, CaV1.2, and CaV1.4 showing lower expression for the former category. Angioimmunoblastic T cell lymphoma showed increased expression of CaV1.4 compared to control T helper cells. As Ca²⁺ is known to bind to calmodulin, leading to calcineurin activation and the direction of nuclear factor of activated T cells (NFAT) to the cell nucleus as its destination, pathways for calcineurin, calmodulin, NFAT, and Ca²⁺ signaling were also analyzed by Gene Set Enrichment Analysis. Within the Ca²⁺ signaling pathway, PRKX, a gene associated with proliferation, was significant. In order to generate new antibody biologics that target individual L-type CaV channels, monoclonal antibodies against the CaV1.1, CaV1.2, CaV1.3, and CaV1.4 channels were created and evaluated. Among the antibodies that were developed, the antibody of clone 1C10 underwent further characterization. This anti-CaV1.4 antibody was effective in inhibiting the viability of P388 pre-B cell lymphoma cells. The 1C10 antibody was also found to affect Ca²⁺ flux in P388 cells and dampen P388 cancer progression in a mouse model. In conclusion, the findings suggest likely L-type CaV channel involvement in lymphoma growth. Furthermore, our results indicate that antibodies against specific L-type Ca²⁺ channels have strong potential therapeutic benefits, such as in the case of the 1C10 antibody and the CaV1.4 channel.

Text

2025-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/73250

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/