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PLCy1/PKC0 Downstream Signaling Controls Cutaneous T-Cell Lymphoma Development and Progression

Abstract: Developing mechanistic rationales can improve the clinical management of cutaneous T-cell lymphomas. There is considerable genetic and biological evidence of a malignant network of signaling mechanisms, highly influenced by deregulated TCR/PLC?1 activity, controlling the biology of these lesions. In addition, activated signal transducer and activator of transcription 3 is associated with clinical progression, although the alterations responsible for this have not been fully elucidated. Here, we studied PLC?1-dependent mechanisms that can mediate STAT3 activation and control tumor growth and progression. Downstream of PLC?1, the pharmacological inhibition and genetic knockdown of protein kinase C theta (PKC?) inhibited signal transducer and activator of transcription 3 activation, impaired proliferation, and promoted apoptosis in cutaneous T-cell lymphoma cells. A PKC?-dependent transcriptome in mycosis fungoides/Sézary syndrome cells revealed potential effector genes controlling cytokine signaling, TP53, and actin cytoskeleton dynamics. Consistently, an in vivo chicken embryo model xenografted with mycosis fungoides cells showed that PKC? blockage abrogates tumor growth and spread to distant organs. Finally, the expression of a number of PKC? target genes found in mycosis fungoides cells significantly correlated with that of PRKCQ (PKC?) in 81 human mycosis fungoides samples. In summary, PKC? can play a central role in the activation of malignant cutaneous T-cell lymphoma mechanisms via multiple routes, including, but not restricted to, STAT3. These mechanisms may, in turn, serve as targets for specific therapies.

 Fuente: J Invest Dermatol . 2022 May;142(5):1391-1400.e15

 Editorial: Elsevier

 Año de publicación: 2022

 Nº de páginas: 25

 Tipo de publicación: Artículo de Revista

 DOI: 10.1016/j.jid.2021.09.024

 ISSN: 0022-202X,1523-1747

 Url de la publicación: https://www.doi.org/10.1016/j.jid.2021.09.024

Autoría

NURIA GARCIA DIAZ

ALONSO-ALONSO, RUTH

LAURA QUEVEDO PALACIO

RODRÍGUEZ, MARTA

FULGENCIO RUSO JULVE

ESTEVE-CODINA, ANNA

GUT, MARTA

GRU, ALEJANDRO A.

MARIA CARMEN GONZALEZ VELA

GUT, IVO

RODRIGUEZ-PERALTO, JOSÉ LUIS

ORTIZ-ROMERO, PABLO LUIS

PIRIS, MIGUEL A.