Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

Abstract

Solid tumors often grow in a micro-environment characterized by < 2% O2 tension. This condition, together with the aberrant activation of specific oncogenic patwhays, increases the amount and activity of the hypoxia-inducible factor-1α (HIF-1α), a transcription factor that controls up to 200 genes involved in neoangiogenesis, metabolic rewiring, invasion and drug resistance. Hypoxia also induces endoplasmic reticulum (ER) stress, a condition that triggers cell death, if cells are irreversibly damaged, or cell survival, if the stress is mild.Hypoxia and chronic ER stress both induce chemoresistance. In this review we discuss the multiple and interconnected circuitries that link hypoxic environment, chronic ER stress and chemoresistance. We suggest that hypoxia and ER stress train and select the cells more adapted to survive in unfavorable conditions, by activating pleiotropic mechanisms including apoptosis inhibition, metabolic rewiring, anti-oxidant defences, drugs efflux. This adaptative process unequivocally expands clones that acquire resistance to chemotherapy.We believe that pharmacological inhibitors of HIF-1α and modulators of ER stress, although characterized by low specificty and anti-cancer efficacy when used as single agents, may be repurposed as chemosensitizers against hypoxic and chemorefractory tumors in the next future.

Targeting the Integrated Stress Response in Cancer Therapy

“…damaged organelles, or intracellular pathogens (Pakos-Zebrucka et al, 2016;Clementi et al, 2020;Akman et al, 2021). Autophagy can be activated both via specific, stimulus-dependent manner and more general, stimulus-independent signaling pathways to coordinate different phases of autophagy.…”

“…ISR is an evolutionarily conserved intra-cellular signal network activated in response to various intrinsic and extrinsic factors (Figure 1). Extrinsic factors include amino acid depletion, glucose deprivation, viral infection, hypoxia, heme deficiency, ROS (reactive oxygen species) and DNA damage (Pakos-Zebrucka et al, 2016;Clementi et al, 2020;Akman et al, 2021). Cellular intrinsic stresses, such as ER (endoplasmic reticulum) stress, can also activate the ISR (Pakos-Zebrucka et al, 2016).…”

Identifying a Hypoxia-Related Long Non-Coding RNAs Signature to Improve the Prediction of Prognosis and Immunotherapy Response in Hepatocellular Carcinoma

“…Accumulative evidence suggests that hypoxia can drive cancer cells to an immune resistance phenotype and is associated with resistance to immunotherapy ( Abou Khouzam, et al, 2020 ). Hypoxia is also involved in the acquired chemoresistance during cancer chemotherapy ( Akman, et al, 2021 ). Therefore, we investigated the association of the hypoxia-related lncRNA signature with immunotherapy response and targeted drug sensitivity in HCC.…”

“…Additionally, the low-risk group exhibits a lower inhibitory concentration (IC 50 ) value of Axitinib, Dasatinib, Erlotinib, Gefitinib, and Lapatinib, suggesting a higher sensitivity to these drugs than the high-risk group. Hypoxia aberrantly activates the HIF-1α pathway and several specific oncogenic pathways, inducing chemoresistance in cancer chemotherapy ( Akman, et al, 2021 ; Kim and Lee, 2017 ). In line with these studies, the high-risk group retains more enriched scores in the “WNT_BETA_CATENIN_SIGNALING” and “PI3K_AKT_MTOR_SIGNALING” pathways, demonstrating the potential chemoresistance mechanism under the hypoxia condition in HCC.…”

Small Molecules Targeting Programmed Cell Death in Breast Cancer Cells

“…Multiple cross-talks between the various pathways of ER-stress suggest the possible association of ER-stress with chemoresistance in tumours [44]. Activation of the ER stress pathways triggers pro-survival signals in tumours, which promote migration and invasion of cancer cells that characterize aggressive cancers [45].…”