mTORC2 regulates ribonucleotide reductase to promote DNA replication and gemcitabine resistance in non-small cell lung cancer
DNA Replication
0301 basic medicine
Antimetabolites, Antineoplastic
Ribonucleoside Diphosphate Reductase
Mechanistic Target of Rapamycin Complex 2
Deoxycytidine
Histones
03 medical and health sciences
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Ribonucleotide Reductases
Humans
Phosphorylation
Ribonucleotide reductase
mTORC2
RC254-282
Original Research
Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Gemcitabine
DNA replication stress
3. Good health
Gene Expression Regulation, Neoplastic
Drug Resistance, Neoplasm
Gene Knockdown Techniques
DNA Damage
Protein Binding
Signal Transduction
DOI:
10.1016/j.neo.2021.05.007
Publication Date:
2021-06-12T00:11:42Z
AUTHORS (16)
ABSTRACT
Ribonucleotide reductase (RNR) is the key enzyme that catalyzes the production of deoxyribonucleotides (dNTPs) for DNA replication and it is also essential for cancer cell proliferation. As the RNR inhibitor, Gemcitabine is widely used in cancer therapies, however, resistance limits its therapeutic efficacy and curative potential. Here, we identified that mTORC2 is a main driver of gemcitabine resistance in non-small cell lung cancers (NSCLC). Pharmacological or genetic inhibition of mTORC2 greatly enhanced gemcitabine induced cytotoxicity and DNA damage. Mechanistically, mTORC2 directly interacted and phosphorylated RNR large subunit RRM1 at Ser 631. Ser631 phosphorylation of RRM1 enhanced its interaction with small subunit RRM2 to maintain sufficient RNR enzymatic activity for efficient DNA replication. Targeting mTORC2 retarded DNA replication fork progression and improved therapeutic efficacy of gemcitabine in NSCLC xenograft model in vivo. Thus, these results identified a mechanism through mTORC2 regulating RNR activity and DNA replication, conferring gemcitabine resistance to cancer cells.
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CITATIONS (10)
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