Autophagy, molecular chaperones, and unfolded protein response as promoters of tumor recurrence

Alhasan, Bashar A.; Mikeladze, Marina A.; Guzhova, Irina V.; Margulis, Boris A.

doi:10.1007/s10555-023-10085-3

Cited by 8 publications

(2 citation statements)

References 381 publications

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“…The data presented here can accomplish the hypothetical picture of events occurring in the tumor according to which monocytes/macrophages and other stromal cells, primarily fibroblasts and neutrophils, undergo rewiring depending on their amount and powerfulness of cancer cells; the balance between these abilities may be established by proteostasis mechanisms, including molecular chaperones governed by HSF1 and autophagy. This process may involve cancer cells even in the very beginning of tumor growth and dissemination, e.g., tumor-initiating cells, stem-like cells and drug-tolerant persisters [ 46 , 47 ].…”

Section: Discussionmentioning

confidence: 99%

Novel mechanism of drug resistance triggered by tumor-associated macrophages through Heat Shock Factor-1 activation

Nikotina,

Vladimirova,

Kokoreva

et al. 2024

Cancer Immunol Immunother

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Macrophages constitute a major part of tumor microenvironment, and most of existing data demonstrate their ruling role in the development of anti-drug resistance of cancer cell. One of the most powerful protection system is based on heat shock proteins whose synthesis is triggered by activated Heat Shock Factor-1 (HSF1); the inhibition of the HSF1 with CL-43 sensitized A549 lung cancer cells to the anti-cancer effect of etoposide. Notably, analyzing A549 tumor xenografts in mice we observed nest-like pattern of co-localization of A549 cells demonstrating enhanced expression of HSF1 with macrophages, and decided to check whether the above arrangement has a functional value for both cell types. It was found that the incubation of A549 or DLD1 colon cancer cells with either human monocytes or THP1 monocyte-like cells activated HSF1 and increased resistance to etoposide. Importantly, the same effect was shown when primary cultures of colon tumors were incubated with THP1 cells or with human monocytes. To prove that HSF1 is implicated in enhanced resistance caused by monocytic cells, we generated an A549 cell subline devoid of HSF1 which did not respond to incubation with THP1 cells. The pharmacological inhibition of HSF1 with CL-43 also abolished the effect of THP1 cells on primary tumor cells, highlighting a new target of tumor-associated macrophages in a cell proteostasis mechanism.

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Section: Discussionmentioning

confidence: 99%

Novel mechanism of drug resistance triggered by tumor-associated macrophages through Heat Shock Factor-1 activation

Nikotina,

Vladimirova,

Kokoreva

et al. 2024

Cancer Immunol Immunother

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“…In many cases, tiny populations of tumor cells constituting so called minimal residual disease, acquire a dormant phenotype that is characterized by extremely low growth and metabolic activity and an increased level of autophagy [ 1 ]. Such cells, known as disseminated tumor cells or drug-tolerant persisters, demonstrate the attributes of cancer stem cells (CSCs) [ 2 , 3 ]. Irrespective of their origin, dormant cells persist in special niches as single cells or sparse colonies (micrometastases) for an indefinite period of time.…”

Section: Introductionmentioning

confidence: 99%

Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex

Sverchinsky,

Alhasan,

Mikeladze

et al. 2023

J Exp Clin Cancer Res

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Background Cancer recurrence is regulated by a variety of factors, among which is the material of dying tumor cells; it is suggested that remaining after anti-cancer therapy tumor cells receive a signal from proteins called damage-associated molecular patterns (DAMPs), one of which is heat shock protein 70 (Hsp70). Methods Two models of tumor repopulation were employed, based on minimal population of cancer cells and application of conditioned medium (CM). To deplete the CMs of Hsp70 affinity chromatography on ATP-agarose and immunoprecipitation were used. Cell proliferation and the dynamics of cell growth were measured using MTT assay and xCELLigence technology; cell growth markers were estimated using qPCR and with the aid of ELISA for prostaglandin E detection. Immunoprecipitation followed by mass-spectrometry was employed to identify Hsp70-binding proteins and protein-protein interaction assays were developed to reveal the above protein complexes. Results It was found that CM of dying tumor cells contains tumor regrowth-initiating factors and the removal of one of them, Hsp70, caused a reduction in the relapse-activating capacity. The pull out of Hsp70 alone using ATP-agarose had no effect on repopulation, while the immunodepletion of Hsp70 dramatically reduced its repopulation activity. Using proteomic and immunochemical approaches, we showed that Hsp70 in conditioned medium binds and binds another abundant alarmin, the High Mobility Group B1 (HMGB1) protein; the complex is formed in tumor cells treated with anti-cancer drugs, persists in the cytosol and is further released from dying tumor cells. Recurrence-activating power of Hsp70-HMGB1 complex was proved by the enhanced expression of proliferation markers, Ki67, Aurka and MCM-10 as well as by increase of prostaglandin E production and autophagy activation. Accordingly, dissociating the complex with Hsp70 chaperone inhibitors significantly inhibited the pro-growth effects of the above complex, in both in vitro and in vivo tumor relapse models. Conclusions These data led us to suggest that the abundance of the Hsp70-HMGB1 complex in the extracellular matrix may serve as a novel marker of relapse state in cancer patients, while specific targeting of the complex may be promising in the treatment of cancers with a high risk of recurrence.

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A new perspective on the autophagic and non-autophagic functions of the GABARAP protein family: a potential therapeutic target for human diseases

et al. 2023

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Autophagy, molecular chaperones, and unfolded protein response as promoters of tumor recurrence

Cited by 8 publications

References 381 publications

Novel mechanism of drug resistance triggered by tumor-associated macrophages through Heat Shock Factor-1 activation

Novel mechanism of drug resistance triggered by tumor-associated macrophages through Heat Shock Factor-1 activation

Autocrine regulation of tumor cell repopulation by Hsp70-HMGB1 alarmin complex

A new perspective on the autophagic and non-autophagic functions of the GABARAP protein family: a potential therapeutic target for human diseases

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