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Cancers (Basel). 2019 Jan 8;11(1). pii: E52. doi: 10.3390/cancers11010052.

Modulation of RAB7A Protein Expression Determines Resistance to Cisplatin through Late Endocytic Pathway Impairment and Extracellular Vesicular Secretion.

Author information

1
Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Lecce-Monteroni 165, 73100 Lecce, Italy. guerraflora@gmail.com.
2
Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Lecce-Monteroni 165, 73100 Lecce, Italy. paianoaurora@hotmail.it.
3
Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Lecce-Monteroni 165, 73100 Lecce, Italy. danilo.migoni@unisalento.it.
4
Department of Medical and Surgical Sciences (DIMEC), Medical Genetics Unit, University Hospital S. Orsola-Malpighi, via Massarenti 9, 40138 Bologna, Italy. giulsgiuls85@gmail.com.
5
Unit of Oncologic Gynecology, S. Orsola-Malpighi Hospital, via Massarenti 13, 40138 Bologna, Italy. myriam.perrone@aosp.bo.it.
6
Unit of Oncologic Gynecology, S. Orsola-Malpighi Hospital, via Massarenti 13, 40138 Bologna, Italy. pierandrea.deiaco@aosp.bo.it.
7
Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Lecce-Monteroni 165, 73100 Lecce, Italy. francescopaolo.fanizzi@unisalento.it.
8
Department of Medical and Surgical Sciences (DIMEC), Medical Genetics Unit, University Hospital S. Orsola-Malpighi, via Massarenti 9, 40138 Bologna, Italy. giuseppe.gasparre3@unibo.it.
9
Department of Biological and Environmental Sciences and Technologies (DiSTeBA), University of Salento, Via Provinciale Lecce-Monteroni 165, 73100 Lecce, Italy. cecilia.bucci@unisalento.it.

Abstract

BACKGROUND:

Cisplatin (CDDP) is widely used in treatment of cancer, yet patients often develop resistance with consequent therapeutical failure. In CDDP-resistant cells alterations of endocytosis and lysosomal functionality have been revealed, although their causes and contribution to therapy response are unclear.

METHODS:

We investigated the role of RAB7A, a key regulator of late endocytic trafficking, in CDDP-resistance by comparing resistant and sensitive cells using western blotting, confocal microscopy and real time PCR. Modulation of RAB7A expression was performed by transfection and RNA interference, while CDDP sensitivity and intracellular accumulation were evaluated by viability assays and chemical approaches, respectively. Also extracellular vesicles were purified and analyzed. Finally, correlations between RAB7A and chemotherapy response was investigated in human patient samples.

RESULTS:

We demonstrated that down-regulation of RAB7A characterizes the chemoresistant phenotype, and that RAB7A depletion increases CDDP-resistance while RAB7A overexpression decreases it. In addition, increased production of extracellular vesicles is modulated by RAB7A expression levels and correlates with reduction of CDDP intracellular accumulation.

CONCLUSIONS:

We demonstrated, for the first time, that RAB7A regulates CDDP resistance determining alterations in late endocytic trafficking and drug efflux through extracellular vesicles.

KEYWORDS:

RAB7A; chemoresistance; cisplatin; endocytosis; lysosome

PMID:
30626032
DOI:
10.3390/cancers11010052
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