nn6b07311_si_001.pdf (1.03 MB)
Graphene Oxide Induced Perturbation to Plasma Membrane and Cytoskeletal Meshwork Sensitize Cancer Cells to Chemotherapeutic Agents
journal contribution
posted on 2017-02-16, 00:00 authored by Jianqiang Zhu, Ming Xu, Ming Gao, Zhihong Zhang, Yong Xu, Tian Xia, Sijin LiuThe
outstanding physicochemical properties endow graphene materials
(e.g., graphene oxide, GO) with beneficial potentials
in diverse biomedical fields such as bioimaging, drug delivery, and
biomolecular detection. GO recently emerged as a chemosensitizer;
however, the detailed molecular basis underlying GO-conducted sensitization
and corresponding biological effects are still elusive. Based on our
recent findings that GO treatment at sublethal concentrations could
impair the general cellular priming state, including disorders of
plasma membrane and cytoskeleton construction, we aimed here to explore
the mechanism of GO as a sensitizer to make cancer cells more susceptible
to chemotherapeutic agents. We discovered that GO could not only compromise
plasma membrane and cytoskeleton in J774A.1 macrophages and A549 lung
cancer cells at sublethal concentrations without incurring significant
cell death but also dampen a number of biological processes. Using
the toxicogenomics approaches, we laid out the gene expression signature
affected by GO and further defined those genes involved in membrane
and cytoskeletal impairments responding to GO. The mechanistic investigation
uncovered that the interactions of GO–integrin occurred on
the plasma membrane and consequently activated the integrin–FAK–Rho–ROCK
pathway and suppressed the expression of integrin, resulting in compromised
cell membrane and cytoskeleton and a subsequent cellular priming state.
By making use of this mechanism, the efficacy of chemotherapeutic
agents (e.g., doxorubicin and cisplatin) could be
enhanced by GO pretreatment in killing cancer cells. This study unveiled
a feature of GO in cancer therapeutics: sensitizing cancer cells to
chemotherapeutic agents by undermining the resistance capability of
tumor cells against chemotherapeutic agents, at least partially, by
compromising plasma membrane and cytoskeleton meshwork.