RESUMO
Mitogen Activated Protein Kinase (MAPK) is one of the most well characterized cellular signaling pathways that controls fundamental cellular processes including proliferation, differentiation, and apoptosis. These cellular functions are consequences of transcription of regulatory genes that are influenced and regulated by the MAP-Kinase signaling cascade. MAP kinase components such as Receptor Tyrosine Kinases (RTKs) sense external cues or ligands and transmit these signals via multiple protein complexes such as RAS-RAF, MEK, and ERKs and eventually modulate the transcription factors inside the nucleus to induce transcription and other regulatory functions. Aberrant activation, dysregulation of this signaling pathway, and genetic alterations in any of these components results in the developmental disorders, cancer, and neurodegenerative disorders. Over the years, the MAPK pathway has been a prime pharmacological target, to treat complex human disorders that are genetically linked such as cancer, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The current review re-visits the mechanism of MAPK pathways in gene expression regulation. Further, a current update on the progress of the mechanistic understanding of MAPK components is discussed from a disease perspective.
Assuntos
Neoplasias , Doenças Neurodegenerativas , Humanos , Proteínas Quinases Ativadas por Mitógeno , Sistema de Sinalização das MAP Quinases/genética , Neoplasias/genética , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/genética , Expressão GênicaRESUMO
Inhibition of mammalian target of rapamycin complex 1 (mTORC1) with rapamycin in the absence of transforming growth factor-ß (TGFß) signaling induces apoptosis in many cancer cell lines. In the presence of TGFß, rapamycin induces G1 cell cycle arrest; however, in the absence of TGFß, cells do not arrest in G1 and progress into S-phase where rapamycin is cytotoxic rather than cytostatic. However, we observed that DU145 prostate and NCI-H2228 lung cancer cells were resistant to the cytotoxic effect of rapamycin. Of interest, the rapamycin-resistant DU145 and NCI-H2228 cells have mutations in the RB and CDKN2A tumor suppressor genes. The gene products of RB and CDKN2A (pRb and p14ARF) suppress E2F family transcription factors that promote cell cycle progression from G1 into S. Restoration of wild type RB or inhibition of E2F activity in DU145 and NCI-H2228 cells led to rapamycin sensitivity. These data provide evidence that the combination of mutant RB and mutant CDKN2A in cancer cells leads to rapamycin resistance, which has implications for precision medicine approaches to anti-cancer therapies.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Proteína do Retinoblastoma/genética , Fator de Crescimento Transformador beta/genética , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fatores de Transcrição E2F/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Mutação/genética , Fosforilação/efeitos dos fármacos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Transdução de Sinais/efeitos dos fármacos , Sirolimo/efeitos adversos , Sirolimo/farmacologiaRESUMO
Prostate cells are hormonally driven to grow and divide. Typical treatments for prostate cancer involve blocking activation of the androgen receptor by androgens. Androgen deprivation therapy can lead to the selection of cancer cells that grow and divide independently of androgen receptor activation. Prostate cancer cells that are insensitive to androgens commonly display metastatic phenotypes and reduced long-term survival of patients. In this study we provide evidence that androgen-insensitive prostate cancer cells have elevated PLD activity relative to the androgen-sensitive prostate cancer cells. PLD activity has been linked with promoting survival in many human cancer cell lines; and consistent with the previous studies, suppression of PLD activity in the prostate cancer cells resulted in apoptotic cell death. Of significance, suppressing the elevated PLD activity in androgen resistant prostate cancer lines also blocked the ability of these cells to migrate and invade Matrigel™. Since survival signals are generally an early event in tumorigenesis, the apparent coupling of survival and metastatic phenotypes implies that metastasis is an earlier event in malignant prostate cancer than generally thought. This finding has implications for screening strategies designed to identify prostate cancers before dissemination.
