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Differential effects of cisplatin on lung cancer cells and primary neurons: roles of small GTPase RhoA
Author(s) -
Weng Zhiying,
Friesland Amy,
Lu Zhe,
Chen YanHua,
Longo Frank M,
Boykin Christi,
Lu Qun
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1105.28
Subject(s) - rhoa , cisplatin , microbiology and biotechnology , apoptosis , neurotoxicity , chemistry , cancer cell , mitochondrion , cancer research , small gtpase , biology , signal transduction , cancer , biochemistry , organic chemistry , chemotherapy , toxicity , genetics
Cisplatin‐induced peripheral neurotoxicity poses a major clinical problem, however cisplatin's mechanism of injury to nonmitotically active neurons is not clear. This study examined differential effects of cisplatin on human lung cancer cell lines and primary mouse neurons. In cancer cells, cisplatin disrupts filamentous‐actin organization and increases G‐actin in the nucleus. Mitochondria aggregated in the cytoplasm yet its matrix components became accumulated in the nucleus accompanying the translocation of actin. In addition, cisplatin selectively activated intrinsic apoptosis pathways of cancer cells but did not activate caspase‐8 mediated cell death, or activate the small GTPase RhoA. LM11A‐31 and Y‐27632, which suppress RhoA signaling, had no effect on lung cancer cell proliferation. The apoptosis pathway activated by cisplatin was also not regulated by LM11A‐31 or Y‐27632. However, in neurons, cisplatin reduced neuronal branching, disrupted growth cone organization, and decreased the amount of G‐actin, all of which can be reversed by RhoA inhibitors. Cisplatin treatment induced mitochondria aggregation and the matrix accumulation in the nucleus. Our studies suggest cisplatin‐induced neurodegeneration correlates with RhoA activation and support RhoA suppression as a potential target for ameliorating cisplatin‐induced neurotoxicity. Supported by NIHCA111891 and NIHCA165202.