Despite diagnostic and therapeutic advances in the last decades, cancer is still one of the deadliest diseases around the world. The lack of a cure for cancer reflects the complexity of its molecular bases, where the deregulation of cellular metabolic pathways is considered one of the emerging hallmarks of the disease. Therefore, there is currently a great demand for a better understanding of the molecular targets and mechanisms related to metabolism in cancer, which may have important roles in cancer progression, resistance and may be aimed for therapy. The mTOR/S6Ks pathway is related to the control of cell growth in response to nutrients, growth factors and cellular energy balance and has been associated with cancer progression and alterations in cancer metabolism. In this project we aim to study important molecular targets related to the mTOR/S6Ks pathway and metabolism control in cancer, amongst them, LKB1, NRF2 and PARP1. LKB1 is an important upstream regulator of the mTOR pathway often mutated in cancer, NRF2, related to oxidative stress, has a dual described relationship with mTOR and cancer and PARP1 has recently been detected as an interacting partner of S6Ks by our group. We intend in this project to genetically alter the expression of those target genes and evaluate effects on cancer metabolism, redox control, DNA repair and the responsiveness of cancer cells to food or plant derived extracts and compounds, including metformin. Moreover, by using a CRISPR/Cas9 library, we will address the resistance of lung cancer cells to cisplatin, detecting possible new target genes related to cancer resistance by a genome-wide approach. Those genes related with cancer metabolism or the mTOR pathway will be preferentially chosen for validation and further exploration as targets for cancer therapy. The results derived from this project may contribute for a better understanding on how cancer cells control metabolism and how this control may be related to the response to natural compounds and chemotherapeutic drugs. (AU)
Articles published in Agência FAPESP Newsletter about the research grant:
PONTE, LUIS GUSTAVO SABOIA;
PAVAN, ISADORA CAROLINA BETIM;
MANCINI, MARIANA CAMARGO SILVA;
DA SILVA, LUIZ GUILHERME SALVINO;
MORELLI, ANA PAULA;
SEVERINO, MATHEUS BRANDEMARTE;
BEZERRA, ROSANGELA MARIA NEVES;
SIMABUCO, FERNANDO MOREIRA.
The Hallmarks of Flavonoids in Cancer.
Web of Science Citations: 3.
DE OLIVEIRA, ANDRESSA PERES;
ISSAYAMA, LUIDY KAZUO;
BETIM PAVAN, ISADORA CAROLINA;
SILVA, FERNANDO RIBACK;
MELO-HANCHUK, TALITA DINIZ;
SIMABUCO, FERNANDO MOREIRA;
Checking NEKs: Overcoming a Bottleneck in Human Diseases.
APR 2 2020.
Web of Science Citations: 1.