The involvement of heat shock proteins and related molecules in the resistance to therapies in breast and gynecologic cancer

The HSP response is implicated in conferring to breast and gynecologic malignancies different sensitivities to anticancer therapies including chemotherapy, endocrine therapy and immunotherapy (weare in the need of more studies about radiotherapy). The heat shock proteins are mainly implicated in cell death mechanisms, in cell differentiation including epithelial-mesenchymal transition, in tumordormancy, in angiogenesis, metastasis formation, and in the escape of immunosurveillance. Considering the ample functions where the HSPs are implicated and that the HSP response is quite complex it is not surprising that the HSP response affects the anticancer therapies. Several of the HSPs have different predominant roles according to the molecular partners with which they interact, thus it is difficult to dissect the molecular mechanisms to find the sensitivity to the therapies. In this review we present the implications of some the major HSPs (HSP27, HSP70 and HSP90) with drug resistance and present some of the main partners that are also implicated in drug resistance like p53, PTEN and MDR. We have given priority to the incorporation of clinical data where the HSPs have been studied using standard chemotherapies and new therapeutic strategies. It is clear that in order to have a significant understanding of the degree of drug resistance/sensitivity presented by a particular patient we need to examine the molecular status of several key molecular markers involved in the drug resistance pathways and that in this context the study of the HSP response should be incorporated. One of the other major problems in this field is that an inhibitor of one particular HSP will not be enough to achieve a significant anticancer response. Now that we know the complexity of this field we need to design strategies aiming to inhibit several molecular HSP pathways simultaneously without significantly affecting the normal cells, this is the principal challenge for the near future.Fil: Cuello Carrión, Fernando Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Fanelli, Mariel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Castro, Gisela Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Cayado Gutiérrez, Niubys de Los Milagros. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Ciocca, Daniel Ramon. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentin

Differential expression and localization of beta-catenin and HSP27 after cisplatin/doxorubicin treatment in triple negative breast cancer cells

The treatment of triple-negative breast cancers involves the administration of the conventional chemotherapeutic drug doxorubicin, given the lack of specific targeted agents. Novel therapeutic strategies, such as cisplatin, are currently being tested for these patients. Many studies have demonstrated that aberrant Wnt/β-catenin signaling serves a role in the development of breast cancer, while others have concluded that abnormal regulation of Wnt pathway induces tumor cell chemoresistance. The small heat shock protein 27 (HSP27) is overexpressed in human breast cancer cells. As a result, cancer cells may suppress apoptosis and develop resistance to antineoplastic agents, such as doxorubicin. The present study sought to examine the role of the Wnt/β-catenin and HSP27 signaling pathway in response to cisplatin (CisPt)/doxorubicin (Doxo) treatment in human triple-negative (TN) breast cancer cell lines. Material and Methods: MDA-MB231 (TN) and MCF10A cell lines were used. Cell viability was measured using MTT assay and IC50 values were obtained after 48 h of CisPt or Doxo exposition. β-catenin and Hsp27 gene expression were measured by qPCR. Total and active β-catenin, phosphor ant total HSP27, phospho and GSK3β, phosphor and total p38 expressions were measured by western blot and immunofluorescence. 3D cell culture from MDA MB231 cells were treated with increasing concentrations of CisPt and Doxo for 48h. Results: MDA-MB231 cells showed higher IC50 values for CisPt and Doxo than the MCF10A cell line. In MDA-MB231 cells, the expression of β-catenin, active β-catenin, total and phospho-GSK3β and total HSP27 significantly decreased in the CisPt group (p<0.05). No changes were observed in Doxo-treated group. In MCF10A cells, the expression levels of total and active β-catenin did not modify with CisPt treatment, but in the Doxo group the proteins evaluated showed a tendency to increase. Also in MCF10A Doxo treatment significantly decreased the expression of GSK3β in comparison with control (p<0.05). In contrast, CisPt administration significantly increased phospho-GSK3β expression respect to the control group (p<0.05). Interestingly, in MDA-MB231 cells the nucleolus appeared disaggregated and active β-catenin increased at this subcellular localization after CisPt and Doxo treatment. In contrast, total β-catenin was preferentially localized in the Golgi. In the other hand 3D cell culture was more resistant to Doxo-treatment than 2D cell culture. CisPt induced a decrease in 3D cell culture growth. Conclusions: CisPt treatment was associated with decreased expression of β-catenin and HSP27. While in Doxo-treated cells, as related to stable levels of β-catenin and increased expression of HSP27. The differential expression and localizations of β-catenin and HSP27 could be related to a differential cellular response depending on the cytotoxicity mechanism of chemotherapeutic agent used., that in turns affect the cell fate decision. Our preliminary data indicate that β-catenin and HSP27 may be potential therapeutic targets in TNBC.Fil: Córdoba, María Evelyn. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Pennacchio, Gisela Erika. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Cayado Gutiérrez, Niubys de Los Milagros. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Cuello Carrión, Fernando Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Nadin, Silvina Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Vargas Roig, María Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Fanelli, Mariel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaXXXVII Reunión Científica Anual de la Sociedad de Biología de CuyoSan LuisArgentinaSociedad de Biología de Cuy

In MMTV-Her-2/neu transgenic mammary tumors the absence of caveolin-1−/− alters PTEN and NHERF1 but not β-catenin expression

In a recent study, we have shown that in mammary tumors from mice lacking the Cav-1 gene, there are alterations in specific heat shock proteins as well as in tumor development. With this in mind, we have now investigated other proteins in the same mammary mouse tumor model (Her-2/neu expressing mammary tumors from Cav-1 wild type and Cav-1 null mice), to further comprehend the complex tumor-stroma mechanisms involved in regulating stress responses during tumor development. In this tumor model the cancer cells always lacked of Cav-1, so the KO influenced the Cav-1 in the stroma. By immunohistochemistry, we have found a striking co-expression of β-catenin and Her-2/neu in the tumor cells. The absence of Cav-1 in the tumor stroma had no effect on expression or localization of β-catenin and Her-2/neu. Both proteins appeared co-localized at the cell surface during tumor development and progression. Since Her-2/neu activation induces MTA1, we next evaluated MTA1 in the mouse tumors. Although this protein was found in numerous nuclei, the absence of Cav-1 did not alter its expression level. In contrast, significantly more PTEN protein was noted in the tumors lacking Cav-1 in the stroma, with the protein localized mainly in the nuclei. P-Akt levels were relatively low in tumors from both Cav-1 WT and Cav-1 KO mice. There was also an increase in nuclear NHERF1 expression levels in the tumors arising from Cav-1 KO mice. The data obtained in the MMTV-neu model are consistent with a role for Cav-1 in adjacent breast cancer stromal cells in modulating the expression and localization of important proteins implicated in tumor cell behavior.Fil: Cuello Carrión, Fernando Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Cayado Gutiérrez, Niubys de Los Milagros. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Natoli, Anthony L. . Peter MacCallum Cancer Centre. Metastasis Research Laboratory; AustraliaFil: Restall, Christina. Peter MacCallum Cancer Centre. Metastasis Research Laboratory; AustraliaFil: Anderson, Robin L.. Peter MacCallum Cancer Centre. Metastasis Research Laboratory; AustraliaFil: Nadin, Silvina Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Alvarez Olmedo, Daiana Gisela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Castro, Gisela N.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Gago, Francisco E.. Facultad de Ciencias Médicas. Universidad Nacional de Cuyo; ArgentinaFil: Fanelli, Mariel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Ciocca, Daniel Ramon. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentin

Implications of heat shock proteins in carcinogenesis and cancer progression

Heat shock proteins (Hsp) participate in many events related to cancer as molecular chaperones, starting from the very beginning of carcinogenesis. Several etiological factors involve the Hsp family in their mechanisms of action, including oncogenic viruses, hereditary and non hereditary alterations in tumor suppressors or oncoproteins, hypermethylation, radiation and carcinogenic agents. All of them produce changes in the Hsp response with consequences in cell proliferation, differentiation, inflammation, apoptosis, DNA repair, angiogenesis, metastasis, and drug resistance and in the immunological response mounted by the host. In this chapter we will examine the participation of the Hsp response in tumor cell transformation, either by up-regulation or down-regulation of specific Hsp. This can explain the variations in Hsp expression found in pre-neoplastic and neoplastic human tumors in different tissues and organs. These variations have important clinical consequences in cancer progression, and the exploitation of such knowledge may improve anticancer treatment strategies.Fil: Ciocca, Daniel Ramon. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Fanelli, Mariel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Cuello Carrión, Fernando Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Calderwood, S. K.. Harvard Medical School; Estados Unidos. University Of Boston. School Of Medicine.; Estados Unido

Small stress proteins, biomarkers of cancer

Many oncogenic agents/events generate in cancer cells stress-responsive proteins, also known as heat shock proteins (HSPs). These proteins are implicated in the genesis as well as in the progression of cancer; the small HSPs share the chaperone activity of the other HSPs and thus the small HSPs should also be described as chaperones of tumorigenesis. Since the small HSPs are found at relatively high levels in tumor cells, the study of the expression of these proteins is of high interest as biomarkers of cancer. In this chapter we have analysed the evidence regarding its usefulness: 1) to detect in fluids and tissues the early changes in cell transformation, 2) to help in the diagnosis of the disease, 3) in predicting the recurrence, aggressiveness and the development of metastasis, and 4) to predict the response to therapies and to monitor the efficacy/safety of therapeutic agents. In breast cancer, earlier studies and more recent proteomic studies reveal that the small HSPs are mainly implicated in the response to therapies, HSPB1 (HSP27) appears as a biomarker of resistance to different anticancer therapies. In other tumors, like in prostate cancer, they appear as biomarkers of disease prognosis, while in uterine cervical cancer HSPB1 appears as a marker of cell differentiation. The molecular pathways implicated in the small HSPs activation and the association of these proteins with other proteins result in a unique molecular context in each cancer cell type and ultimately in each patient appearing as biomarkers of different situations. Overall, it is evident that more studies on the topic of biomarkers of anticancer therapies are needed to change the way we treat cancer patients, but so far it seems that the small HSPs, in conjunction with other biomarkers, have a great future to achieve tailored-treatment strategies.Fil: Ciocca, Daniel Ramon. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Fanelli, Mariel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Cuello Carrión, Fernando Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Castro, Gisela Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentin

Heat shock proteins in prostate cancer: From tumorigenesis to the clinic

The heat shock proteins (HSP) constitute a superfamily of chaperone proteins present in all cells and in all cell compartments, operating in a complex interplay with synergistic/overlapping multiplicity of functions, even though the common effect is cell protection. Several reasons explain the need for investigating HSP in prostate cancer: (1) these molecules function as chaperones of tumorigenesis accompanying the emergence of prostate cancer cells, (2) they appear as useful molecular markers associated with disease aggressiveness and with resistance to anticancer therapies including hormone therapy, radiotherapy, chemotherapy and hyperthermia, and (3) they can be used as targets for therapies. The latter can be accomplished by: (i) interrupting the interaction of HSP (mainly HSPC1) with various client proteins that are protected from degradation when chaperoned by the HSP; (ii) using the chaperone and adjuvant capabilities of certain HSP to present antigenic peptides to the immune system, so this system can recognise the prostate tumour cells as foreign to mount an effective antitumoral response; and (iii) using treatment planning models taking into account the HSP expression levels to obtain more effective therapies. In summary, the study of the HSP during tumorigenesis as well as during cancer progression, and the inclusion of treatment designs targeting HSP combined with other treatment modalities, should improve prostate cancer survival in the near future.Fil: Ciocca, Daniel Ramon. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Fanelli, Mariel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Cuello Carrión, Fernando Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Castro, Gisela Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentin

Metalloproteomics analysis in human mammary cell lines treated with inorganic mercury

The interest in inorganic Hg toxicity and carcinogenicity has been pointed to target organs such as kidney, brain or placenta, but only a few studies have focused on the mammary gland. In this work, analytical combination techniques (SDS-PAGE followed by CV-AFS, and nanoUPLC-ESI-MS/MS) were used to determine proteins that could bind Hg in three human mammary cell lines. Two of them were tumorigenic (MCF-7 and MDA-MB-231) and the other one was the non-tumorigenic cell line (MCF-10A). There are no studies that provide this kind of information in breast cell lines with IHg treatment. Previously, we described the viability, uptake and the subcellular distribution of Hg in human breast cells and analysis of RNA-seq about the genes that encode proteins which are related to cytotoxicity of Hg. This work provides important protein candidates for further studies of Hg toxicity in the mammary gland, thus expanding our understanding of how environmental contaminants might affect tumor progression and contribute with future therapeutic methods.Fil: Ávila Maniero, Mariángeles. Universidad "Juan Agustín Maza"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Interdisciplinario de Ciencias Básicas. - Universidad Nacional de Cuyo. Instituto Interdisciplinario de Ciencias Básicas; ArgentinaFil: Wuilloud, Rodolfo German. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Interdisciplinario de Ciencias Básicas. - Universidad Nacional de Cuyo. Instituto Interdisciplinario de Ciencias Básicas; ArgentinaFil: Callegari, Eduardo Alberto. University of South Dakota; Estados UnidosFil: Smichowski, Patricia Nora. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Fanelli, Mariel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentin

Heat shock protein 27 modulates autophagy and promotes cell survival after photodynamic therapy

Photodynamic therapy (PDT) is a clinically approved treatment that exerts a selective cytotoxic activity toward cancer cells. The procedure involves the administration of a photosensitizer drug followed by its activation by visible light. In the presence of oxygen, a series of events lead to tumor cell death. PDT releases different cell signals, some of these lead to death while others can lead to survival. The surviving or resistant cells contribute to the recurrence of tumors after treatment, from which the necessity to understand this molecular response induced by PDT arises. It has been shown that both Heat Shock Proteins (HSPs) and autophagy promote PDT resistance. Moreover, both of them can be stimulated by PDT treatment. However, the molecular interplay between HSPs and autophagy in the photodynamic therapy context is poorly understood. We studied whether PDT induces autophagic activity through HSPs. We demonstrated that PDT promoted HSP27 expression, which in turn triggered autophagic cell survival as well as inhibited apoptosis in colon cancer cells. In addition, an overexpression of the HSP27/autophagy axis was observed in skin carcinoma cells resistant to PDT.Fil: Rodriguez, Matias Exequiel. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Arévalo, Daniela Elisa. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; ArgentinaFil: Milla Sanabria, Laura Natalia. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; ArgentinaFil: Cuello Carrión, Fernando Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Fanelli, Mariel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Rivarola, Viviana Alicia. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Departamento de Biología Molecular; Argentin

Heat shock factor 1 represses estrogen-dependent transcription through association with MTA1

Heat shock factor 1 (HSF1), the transcriptional activator of the heat shock genes, is increasingly implicated in cancer. We have shown that HSF1 binds to the corepressor metastasis-associated protein 1 (MTA1) in vitro and in human breast carcinoma samples. HSF1-MTA1 complex formation was strongly induced by the transforming ligand heregulin and complexes incorporated a number of additional proteins including histone deacetylases (HDAC1 and 2) and Mi2α, all components of the NuRD corepressor complex. These complexes were induced to assemble on the chromatin of MCF7 breast carcinoma cells and associated with the promoters of estrogen-responsive genes. Such HSF1 complexes participate in repression of estrogen-dependent transcription in breast carcinoma cells treated with heregulin and this effect was inhibited by MTA1 knockdown. Repression of estrogen-dependent transcription may contribute to the role of HSF1 in cancer.Fil: Khaleque, M. A.. Harvard Medical School; Estados Unidos. North South University; BangladeshFil: Bharti, A.. Boston University; Estados UnidosFil: Gong, J.. Boston University; Estados UnidosFil: Gray, P. J.. Harvard Medical School; Estados UnidosFil: Sachdev, V.. Boston University; Estados UnidosFil: Ciocca, Daniel Ramon. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Stati, Arturo Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Fanelli, Mariel Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Calderwood, S. K.. Boston University; Estados Unidos. Harvard Medical School; Estados Unido

Hyperthermia effects on Hsp27 and Hsp72 associations with mismatch repair (MMR) proteins and cisplatin toxicity in MMR-deficient/proficient colon cancer cell lines

Purpose: Hyperthermia is used in combination with conventional anticancer agents to potentiate their cytotoxicity. One of its key events is the synthesis of heat shock proteins (HSPs), which are able to associate with components from DNA repair mechanisms. However, little is known about their relationship with the mismatch repair system (MMR). Our aim was to study the effects of hyperthermia on cisplatin (cPt) sensitivity and to determine whether MLH1 and MSH2 associate with Hsp27 and Hsp72 in MMR-deficient(-)/-proficient(+) cells.Materials and methods: HCT116+ch2 (MMR-) and HCT116+ch3 (MMR+) cell lines were exposed to cPt with or without previous hyperthermia (42 °C, 1 h). Clonogenic survival assays, MTT, confocal immunofluorescence, immunoprecipitation, immunoblotting and flow cytometry were performed.Results: Hyperthermia increased the cPt resistance in MMR- cells 1.42-fold. Immunofluorescence revealed that after cPt, Hsp27 and Hsp72 translocated to the nucleus and colocalisation coefficients between these proteins with MLH1 and MSH2 increased in MMR+ cells. Immunoprecipitation confirmed the interactions between HSPs and MMR proteins in control and treated cells. Hyperthermia pretreatment induced cell cycle arrest, increased p73 expression and potentiated cPt sensitivity in MMR+ cells.Conclusions: This is the first report showing in a MMR-/+ cellular model that MLH1 and MSH2 are client proteins of Hsp27 and Hsp72. Our study suggests that p73 might participate in the cellular response to hyperthermia and cPt in a MMR-dependent manner. Further functional studies will confirm whether HSPs cooperate with the MMR system in cPt-induced DNA damage response or whether these protein interactions are only the result of their chaperone functions.Fil: Sottile Fleury, Mayra Lis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Losinno, Antonella Denise. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Fanelli, Mariel Andrea. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Cuello Carrión, Fernando Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Montt Guevara, Maria Magdalena. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Vargas Roig, Laura Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas; ArgentinaFil: Nadin, Silvina Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; Argentin