Identification of Potential Chemical Substrates as Fuel for Hypoxic Tumors That May Be Linked to Invadopodium Formation in Hypoxia-Induced MDA-MB-231 Breast-Cancer Cell Line.

Hamad Ali Hamad,Hamid Hammad Enezei,Nurul Akmaryanti Abdullah,Noraina Muhamad Zakuan,Anmar Alrawas,Yoke Kqueen Cheah,Nur Fariesha Md Hashim

doi:10.3390/molecules25173876

Hamad Ali Hamad, Hamid Hammad Enezei + Show 5 more

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https://doi.org/10.3390/molecules25173876

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Abstract

Hypoxia plays a significant role in solid tumors by the increased expression of hypoxia-inducible factor-1α (HIF-1α), which is known to promote cancer invasion and metastasis. Cancer-cell invasion dynamically begins with the degradation of the extracellular matrix (ECM) via invadopodia formation. The chemical substrates that are utilized by hypoxic cells as fuel to drive invadopodia formation are still not fully understood. Therefore, the aim of the study was to maintain MDA-MB-231 cells under hypoxia conditions to allow cells to form a large number of invadopodia as a model, followed by identifying their nutrient utilization. The results of the study revealed an increase in the number of cells forming invadopodia under hypoxia conditions. Moreover, Western blot analysis confirmed that essential proteins for hypoxia and invadopodia, including HIF-1α, vascular endothelial growth factor (VEGF), metallopeptidase-2 (MMP-2), and Rho guanine nucleotide exchange factor 7 (β-PIX), significantly increased under hypoxia. Interestingly, phenotype microarray showed that only 11 chemical substrates from 367 types of substrates were significantly metabolized in hypoxia compared to in normoxia. This is thought to be fuel for hypoxia to drive the invasion process. In conclusion, we found 11 chemical substrates that could have potential energy sources for hypoxia-induced invadopodia formation of these cells. This may in part be a target in the hypoxic tumor and invadopodia formation. Additionally, these findings can be used as potential carrier targets in cancer-drug discovery, such as the usage of dextrin.

Highlights

Hypoxia is observed in the majority of solid tumors
Results revealed that the number of MDA-MB-231 cells forming invadopodia was significantly high for cells incubated with the hypoxia chamber for (3–48) h compared to in normoxia (Figure 1B)
Are essential for invadopodia formation in MDA-MB-231 cells [23,24]. We investigated these two proteins under hypoxia conditions to confirm that the molecular component of invadopodia increases under hypoxia

Summary

Introduction

Hypoxia is observed in the majority of solid tumors. Aggressiveness, angiogenic activity, and tumor progression (enhanced due to low-oxygen) exist in most if not all malignant cancers that are known to resist chemotherapy and radiotherapy. Studies reported that hypoxia is a driving force for breast-cancer progression [1,2]. Previous studies showed that hypoxia-inducible factor-1α (HIF-1α), a master regulator protein in hypoxia, plays an essential role in cancer invasion and metastasis, and evidence suggests that high HIF-1α expression displays poor. Hypoxia in solid tumors can alter cancer-cell metabolism and contributes to therapy resistance by inducing cell quiescence [6]. The adaptation of tumor cells to hypoxia is believed to be the main driver for the selection of more invasive and therapy-resistant phenotypes [8]

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