TM9SF4 is a novel V-ATPase-interacting protein that modulates tumor pH alterations associated with drug resistance and invasiveness of colon cancer cells

Lozupone, Francesco; Borghi, Martina; Marzoli, Francesca; Azzarito, Tommaso; Matarrese, Paola; Iessi, Elisabetta; Venturi, Giulietta; Meschini, Stefania; Canitano, Andrea; Bona, Roberta; Cara, Andrea; Fais, Stefano

doi:10.1038/onc.2014.437

Cited by 74 publications

(62 citation statements)

References 52 publications

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“…TM9SF4 knockdown is associated with a significant inhibition of the invasive behavior of colon cancer cells and with increased sensitivity to the effect of chemotherapeutics. These effects were also consistent with reversing tumor pH gradient with a decrease of cytosolic pH, alkalization of intracellular vesicles and a reduction of extracellular acidity 29 , further supporting the importance of TM9SF4 as a potential target for future anticancer therapies. All in all this line of research, that started simply from the microscopic observation of the cells within other cells, has led to the discovery of a new oncoprotein involved in a key function DOI: 10.3109/14756366.2016.1156105 of malignant cells, that is the ability to feed on other cells, probably representing a very important butt for future anticancer therapies, whose discovery was achieved through a definitive nonmainstream way of doing research in medicine.…”

Section: Example 2: Cancer Cells Behave As Amoebassupporting

confidence: 60%

“…This line of research has led to the discovery of a protein that amoebas and cancer cells share, TM9SF4 28 , that is related to their ability, to cannibalize other cells 26 . More recently, the same line of research has shown that TM9SF4 represents a novel V-ATPase-associated protein involved in V-ATPase activation 29 . V-ATPase is a proton pump highly active in malignant tumors we have shown to be a target, while not fully specific, of PPI 9,11 .…”

Section: Example 2: Cancer Cells Behave As Amoebasmentioning

confidence: 97%

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A nonmainstream approach against cancer

Fais

2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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The discovery of antibiotics as specific and effective drugs against infectious agents has generated the belief that the famous Paul Erlich theory on magic bullet should be applied to cancer as well. However, after around 60 years of failures in finding a magic bullet against cancer, a question appears mandatory: does the magic bullet against cancer really exist? In trying to understand more on the issue, we propose three discoveries are coming from a nonmainstream approach against cancer. Tumor is acidic, and tumor acidity impairs drugs entering within tumor cells and isolates tumors from the rest of the body. Proton pumps are key in allowing tumor cells to live in the acidic microenvironment. A class of antiacidic drugs, proton pump inhibitors (PPIs), were shown to have a potent anti-tumor effect, through inhibition of proton pumps in tumor cells. PPIs are indeed prodrugs needing acidity to be activated into the active molecule. So they use protonation by H+ as an activating mechanism, while the vast majority of drugs are totally neutralized by protonation. An anti-tumor therapy based on PPI showed to be effective both in vitro and in vivo. Differently from normal cells, cancer cells meet their energy needs in great part by fermentation, and it appears conceivable that hypoxia and low nutrient transform tumor cells into fermenting anaerobes. This suggests that cancer cells are more similar to unicellular organisms, aimed at surviving in a continuous fighting, rather than cooperating, with other cells, as it occurs in the normal homeostasis of our body. We have shown that cancer cells take their fuel by ''cannibalizing'' other cells, either dead or alive, especially when starved and in acidic condition. This finding led to the discovery of a new oncogene TM9SF4 that human malignant cell shares with amoebas. The evidence is accumulating that almost all the cells release extracellular vehicles (EVs), from micro-to nanosize, which shuttle a variety of molecules. Tumor cells, particularly when stressed in their hostile microenvironment, release high levels of EVs, able to interact with target cells in various ways, within an organ or at a distance. They may represent both valuable tumor biomarker and shuttles for drugs with anti-tumor properties. This article wants to burst a real change in future anti-cancer strategies, based on the idea that tumors are much more common features than specific molecular targets.

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Section: Example 2: Cancer Cells Behave As Amoebassupporting

confidence: 60%

Section: Example 2: Cancer Cells Behave As Amoebasmentioning

confidence: 97%

A nonmainstream approach against cancer

Fais

2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Finally, the transmembrane protein TM9SF4 has been shown to interact with the V-ATPase and modulate activity through regulation of pump assembly. Silencing of TM9SF4 in colon cancer cells reduces in vitro invasiveness (103). Thus the roles of V-ATPases in promoting tumor cell invasion and migration may be complex, and additional studies will be required to fully elucidate these roles.…”

Section: Mechanism Of V-atpase Promotion Of Tumor Cell Invasion Anmentioning

confidence: 98%

“…In ER␣ϩ breast cancer patients, a molecular subtype which makes up ϳ70% of all breast cancers, DMXL2 is upregulated in the 40% of these patients who continue to progress on therapy (40). Targeting the transmembrane protein TM9SF4, another positive enhancer of V-ATPase activity, increases drug sensitivity (103).…”

Section: Function Of V-atpases In Cancermentioning

confidence: 99%

The Function of V-ATPases in Cancer

Stransky

Cotter

Forgac

2016

Physiological Reviews

234

268

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The vacuolar ATPases (V-ATPases) are a family of proton pumps that couple ATP hydrolysis to proton transport into intracellular compartments and across the plasma membrane. They function in a wide array of normal cellular processes, including membrane traffic, protein processing and degradation, and the coupled transport of small molecules, as well as such physiological processes as urinary acidification and bone resorption. The V-ATPases have also been implicated in a number of disease processes, including viral infection, renal disease, and bone resorption defects. This review is focused on the growing evidence for the important role of V-ATPases in cancer. This includes functions in cellular signaling (particularly Wnt, Notch, and mTOR signaling), cancer cell survival in the highly acidic environment of tumors, aiding the development of drug resistance, as well as crucial roles in tumor cell invasion, migration, and metastasis. Of greatest excitement is evidence that at least some tumors express isoforms of V-ATPase subunits whose disruption is not lethal, leading to the possibility of developing anti-cancer therapeutics that selectively target V-ATPases that function in cancer cells.

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“…V‐ATPase function has also been demonstrated to be influenced by the transmembrane protein TM9SF4 and ceramide synthase (LASS2/TMSG1) although the molecular basis for these functional links remain only partially understood 25, 26…”

Section: V‐atpase Structure and Function In Normal Physiologymentioning

confidence: 99%

Vacuolar ATPase as a potential therapeutic target and mediator of treatment resistance in cancer

et al. 2018

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Vacuolar ATPase (V‐ATPase) is an ATP‐dependent H+‐transporter that pumps protons across intracellular and plasma membranes. It consists of a large multi‐subunit protein complex and influences a wide range of cellular processes. This review focuses on emerging evidence for the roles for V‐ATPase in cancer. This includes how V‐ATPase dysregulation contributes to cancer growth, metastasis, invasion and proliferation, and the potential link between V‐ATPase and the development of drug resistance.

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TM9SF4 is a novel V-ATPase-interacting protein that modulates tumor pH alterations associated with drug resistance and invasiveness of colon cancer cells

Cited by 74 publications

References 52 publications

A nonmainstream approach against cancer

A nonmainstream approach against cancer

The Function of V-ATPases in Cancer

Vacuolar ATPase as a potential therapeutic target and mediator of treatment resistance in cancer

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