The Emerging Role of p38 Alpha in Cancer Specific Metabolism and Therapy: Analysis of Autophagic and Apoptotic Pathways in Response to Its Inhibition

Matrone, Antonio (2013). The Emerging Role of p38 Alpha in Cancer Specific Metabolism and Therapy: Analysis of Autophagic and Apoptotic Pathways in Response to Its Inhibition. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f0bb

Abstract

Cancer is one of the leading cause of death in the world. Since tumorigenesis was described as a multistep mechanism in 1958 by Foulds, important progresses are obtained in the research field. Through these years many altered mechanisms were discovered revealing a very intricate picture of this disease. Mutations, epigenetic changes, aneuploidy imply severe modifications in naive cellular pathways involved in every feature of cell life.

p38 MAPK is a family of kinases composed by four isoforms: alpha, beta, delta and gamma. These kinases are involved in several important cellular pathways, from the differentiation of muscle cells to inflammation and also in cancer progression. The pharmacologic and genetic inhibition of p38 alpha in colorectal cancer cells induced cell cycle arrest, autophagy and then cell death with autophagic features.

My PhD project is focused on the understanding the role of p38 alpha in the autophagic activation in colorectal cancer cell lines, finding that its inhibition induced the decrease of HIF-1 alpha protein levels and its glycolytic transcriptional program. Moreover, p38 alpha inhibition trigger the activation of FoxO3A-dependent transcription, which is related to cell cycle arrest, autopahgy and cell death. We checked for other HIF-1 alpha-dependent tumors which shown also overactivation of p38 alpha, such as ovarian cancer and prostate cancer. In these kind of tumors we obtained the same encouraging results.

However, in the DU 145 prostate cancer cell line, the inhibition of p38 alpha failed to activate autophagic pathway due to the lack of LKB1 kinase, which is the upstream activator of AMPK. In this cell line the inhibition of p38 alpha triggered apoptotic pathway. Chemoresistance is one of the main obstacle in the treatment of cancer. A part of my PhD project is based on the study of p38 alpha role in cisplatin chemoresistance in colorectal cancer cells. Surprisingly, we found that its inhibition, together with the administration of cisplatin, induced apoptotic cell death in the resistant HT29 cell line and increased the effect of cell death in the responsive HCT116 cell line, through the activation of FoxO3A. All these evidences indicated that inhibition of p38 alpha could be used as a promising therapeutic approaches for colorectal cancer and other malignancy, through the activation of FoxO3A-dependent transcription program.

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