Acetyltanshinone IIA reduces the synthesis of cell cycle-related proteins by degrading p70S6K and subsequently inhibits drug-resistant lung cancer cell growth

Bin Huang; Meng Hao; Chuwen Li; Kathy Qian Luo

doi:10.1016/j.phrs.2022.106209

Acetyltanshinone IIA reduces the synthesis of cell cycle-related proteins by degrading p70S6K and subsequently inhibits drug-resistant lung cancer cell growth

Pharmacol Res. 2022 May:179:106209. doi: 10.1016/j.phrs.2022.106209. Epub 2022 Apr 6.

Authors

Bin Huang¹, Meng Hao¹, Chuwen Li², Kathy Qian Luo³

Affiliations

¹ Faculty of Health Sciences, University of Macau, Taipa, Macao Special Administrative Region of China.
² State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao Special Administrative Region of China.
³ Faculty of Health Sciences, University of Macau, Taipa, Macao Special Administrative Region of China. Electronic address: kluo@um.edu.mo.

PMID: 35398238
DOI: 10.1016/j.phrs.2022.106209

Abstract

Targeted therapies using tyrosine kinase inhibitors (TKIs) against epidermal growth factor receptor (EGFR) have improved the outcomes of patients with non-small cell lung cancer (NSCLC). However, due to genetic mutations of EGFR or activation of other oncogenic pathways, cancer cells can develop resistance to TKIs, resulting in usually temporary and reversible therapeutic effects. Therefore, new anticancer agents are urgently needed to treat drug-resistant NSCLC. In this study, we found that acetyltanshinone IIA (ATA) displayed much stronger potency than erlotinib in inhibiting the growth of drug-resistant NSCLC cells and their-derived xenograft tumors. Our analyses revealed that ATA achieved this effect by the following mechanisms. First, ATA could bind p70S6K at its ATP-binding pocket to prevent phosphorylation, and second by increasing the ubiquitination of p70S6K to cause its degradation. Since phosphorylation of S6 ribosome protein (S6RP) by p70S6K can induce protein synthesis at the ribosome, the dramatic reduction of p70S6K after ATA treatment led to great reductions of new protein synthesis on several cell cycle-related proteins including cyclin D3, aurora kinase A, polo-like kinase, cyclin B1, survivin; and reduced the levels of EGFR and MET. In addition, ATA treatment increased the levels of p53 and p21 proteins, which blocked cell cycle progression in the G1/S phase. Taken together, as ATA can effectively block multiple signaling pathways essential for protein synthesis and cell proliferation, ATA can potentially be developed into a multi-target anti-cancer agent to treat TKI-resistant NSCLC.

Keywords: Acetyltanshinone IIA; Afatinib (PubChem CID: 10184653); Aurora kinase A; Drug-resistant lung cancer; EGFR; Erlotinib (PubChem CID: 176870); LY294002 (PubChem CID: 3973); MLN8237 (PubChem CID: 24771867); Osimertinib (PubChem CID: 71496458); P70S6K; PF-4708671 (PubChem CID: 51371303); Rapamycin (PubChem CID: 5284616); Tanshinone IIA (PubChem CID: 164676).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Carcinoma, Non-Small-Cell Lung* / pathology
Cell Cycle
Cell Line, Tumor
Drug Resistance, Neoplasm
ErbB Receptors / metabolism
Humans
Lung Neoplasms* / pathology
Mutation
Phenanthrenes
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Ribosomal Protein S6 Kinases, 70-kDa

Substances

Antineoplastic Agents
Phenanthrenes
Protein Kinase Inhibitors
acetyltanshinone IIA
ErbB Receptors
Ribosomal Protein S6 Kinases, 70-kDa