TY - JOUR
T1 - Loss of Aurora Kinase Signaling Allows Lung Cancer Cells to Adopt Endoreplication and Form Polyploid Giant Cancer Cells That Resist Antimitotic Drugs
AU - Tagal, Vural
AU - Roth, Michael G.
N1 - Funding Information:
We thank Bruce Posner and the personnel of the Simmons Comprehensive Cancer Center High-Throughput Screening Core Facility for aid in dose–response experiments on the NSCLC cell line panel. The human tumor-derived cell panel was created by Drs. John D. Minna and Adi F. Gazdar. We thank our colleague Iryna Zubovych for critical comments. This work was supported by grants CA176284 and CA221978 (to M.G. Roth).
Publisher Copyright:
©2020 American Association for Cancer Research.
PY - 2021/1/15
Y1 - 2021/1/15
N2 - Polyploid giant cancer cells (PGCC) are common in tumors and have been associated with resistance to cancer therapy, tumor relapse, malignancy, immunosuppression, metastasis, cancer stem cell production, and modulation of the tumor microenvironment. However, the molecular mechanisms that cause these cells to form are not yet known. In this study, we discover that Aurora kinases are synergistic determinants of a switch from the proliferative cell cycle to polyploid growth and multinucleation in lung cancer cell lines. When Aurora kinases were inhibited together, lung cancer cells uniformly grew into multinucleated PGCCs. These cells adopted an endoreplication in which the genome replicates, mitosis is omitted, and cells grow in size. Consequently, such cells continued to safely grow in the presence of antimitotic agents. These PGCC re-entered the proliferative cell cycle and grew in cell number when treatment was terminated. Thus, PGCC formation might represent a fundamental cellular response to Aurora kinase inhibitors and contributes to therapy resistance or tumor relapse. Significance: These findings provide a novel insight about how cancer cells respond to Aurora kinase inhibitors and identify a new mechanism responsible for resistance to these agents and other antimitotic drugs.
AB - Polyploid giant cancer cells (PGCC) are common in tumors and have been associated with resistance to cancer therapy, tumor relapse, malignancy, immunosuppression, metastasis, cancer stem cell production, and modulation of the tumor microenvironment. However, the molecular mechanisms that cause these cells to form are not yet known. In this study, we discover that Aurora kinases are synergistic determinants of a switch from the proliferative cell cycle to polyploid growth and multinucleation in lung cancer cell lines. When Aurora kinases were inhibited together, lung cancer cells uniformly grew into multinucleated PGCCs. These cells adopted an endoreplication in which the genome replicates, mitosis is omitted, and cells grow in size. Consequently, such cells continued to safely grow in the presence of antimitotic agents. These PGCC re-entered the proliferative cell cycle and grew in cell number when treatment was terminated. Thus, PGCC formation might represent a fundamental cellular response to Aurora kinase inhibitors and contributes to therapy resistance or tumor relapse. Significance: These findings provide a novel insight about how cancer cells respond to Aurora kinase inhibitors and identify a new mechanism responsible for resistance to these agents and other antimitotic drugs.
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U2 - 10.1158/0008-5472.CAN-20-1693
DO - 10.1158/0008-5472.CAN-20-1693
M3 - Article
C2 - 33172929
AN - SCOPUS:85100424776
SN - 0008-5472
VL - 81
SP - 400
EP - 413
JO - Cancer research
JF - Cancer research
IS - 2
ER -