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Genome editing of LKB1 gene by CRISPR/Cas9 in lung cancer cells and evaluation of its role in metformin and cisplatin response

Grant number: 20/13660-2
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): March 01, 2021
Effective date (End): October 31, 2023
Field of knowledge:Health Sciences - Nutrition - Nutrition Biochemistry
Principal Investigator:Fernando Moreira Simabuco
Grantee:Matheus Brandemarte Severino
Host Institution: Faculdade de Ciências Aplicadas (FCA). Universidade Estadual de Campinas (UNICAMP). Limeira , SP, Brazil
Associated research grant:18/14818-9 - Study of molecular targets important for the control of cancer metabolism: the mTOR/S6K pathway as a central role, AP.JP2
Associated scholarship(s):22/09195-8 - Genome editing of LKB1 gene by CRISPR/Cas9 in lung cancer in vivo and evaluation of its role in metformin response, BE.EP.MS

Abstract

LKB1 is an important upstream inhibitor of the mTOR/S6Ks pathway. Loss of LKB1 is often associated with cancer, including in A549 lung cancer cell line, boosting the transformation of pre-malignant neoplasic cells. Metformin, a natural compound derived from Galega officinalis, is mainly used as a treatment for diabetes mellitus type 2 (DM2), but recently, it has been associated to lower incidence of cancer. One of the main mechanisms is by activation of AMPK through different pathways, including LKB1 activation. Activation of AMPK inhibits the mTOR pathway, protein synthesis and thus cell growth. The combination of metformin and cisplatin, a main chemothepeutic drug for lung cancer, has shown to improve treatment of cancer cells to cisplatin and also to hinder the cisplatin associated resistance common in lung cancer. Here we aim to use the CRISPR/Cas9 technology to correct the mutation presented in A549 lung cancer cells and improve their response to metformin or to the combination between metformin and cisplatin. Besides, we will assess the mTOR signaling pathway status, as well as cell growth, proliferation, cell cycle and sensitivity to apoptosis induction by cisplatin. This project may be useful as a proof of principle that in the future therapies must consider the genomic background of cancer cells before administration of a specific anticancer drug. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MANCINI, MARIANA C. S.; MORELLI, ANA P.; SEVERINO, MATHEUS B.; PAVAN, ISADORA C. B.; ZAMBALDE, ERIKA P.; GOIS, MARIANA M.; DA SILVA, LUIZ G. S.; QUINTERO-RUIZ, NATHALIA; ROMEIRO, CAIO F.; DOS SANTOS JR, DANIEL F. G.; et al. Knockout of NRF2 triggers prostate cancer cells death through ROS modulation and sensitizes to cisplatin. Journal of Cellular Biochemistry, v. 123, n. 12, p. 14-pg., . (20/09310-6, 20/09133-7, 16/06457-0, 20/13660-2, 20/09527-5, 15/00311-1, 20/08684-0, 18/14818-9, 19/00607-9, 19/25582-9, 19/25731-4)

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