Membrane-bound TNF mediates microtubule-targeting chemotherapeutics-induced cancer cytolysis via juxtacrine inter-cancer-cell death signaling

Abstract Microtubule-targeting agents (MTAs) are a class of most widely used chemotherapeutics and their mechanism of action has long been assumed to be mitotic arrest of rapidly dividing tumor cells. In contrast to such notion, here we show—in many cancer cell types—MTAs function by triggering membrane TNF (memTNF)-mediated cancer-cell-to-cancer-cell killing, which differs greatly from other non-MTA cell-cycle-arresting agents. The killing is through programmed cell death (PCD), either in way of necroptosis when RIP3 kinase is expressed, or of apoptosis in its absence. Mechanistically, MTAs induce memTNF transcription via the JNK-cJun signaling pathway. With respect to chemotherapy regimens, our results establish that memTNF-mediated killing is significantly augmented by IAP antagonists (Smac mimetics) in a broad spectrum of cancer types, and with their effects most prominently manifested in patient-derived xenograft (PDX) models in which cell–cell contacts are highly reminiscent of human tumors. Therefore, our finding indicates that memTNF can serve as a marker for patient responsiveness, and Smac mimetics will be effective adjuvants for MTA chemotherapeutics. The present study reframes our fundamental biochemical understanding of how MTAs take advantage of the natural tight contact of tumor cells and utilize memTNF-mediated death signaling to induce the entire tumor regression.

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Cold Physical Plasma in Cancer Therapy: Mechanisms, Signaling, and Immunity

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/9916796 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Fatemeh Faramarzi ◽

Parisa Zafari ◽

Mina Alimohammadi ◽

Mohammadreza Moonesi ◽

Alireza Rafiei ◽

...

Keyword(s):

Cell Death ◽

Immune System ◽

Cancer Therapy ◽

Plasma Treatment ◽

Tumor Cells ◽

Cancer Cell ◽

Intracellular Signaling ◽

Current Knowledge ◽

Cancer Cell Death ◽

Physical Plasma

Despite recent advances in therapy, cancer still is a devastating and life-threatening disease, motivating novel research lines in oncology. Cold physical plasma, a partially ionized gas, is a new modality in cancer research. Physical plasma produces various physicochemical factors, primarily reactive oxygen and nitrogen species (ROS/RNS), causing cancer cell death when supplied at supraphysiological concentrations. This review outlines the biomedical consequences of plasma treatment in experimental cancer therapy, including cell death modalities. It also summarizes current knowledge on intracellular signaling pathways triggered by plasma treatment to induce cancer cell death. Besides the inactivation of tumor cells, an equally important aspect is the inflammatory context in which cell death occurs to suppress or promote the responses of immune cells. This is mainly governed by the release of damage-associated molecular patterns (DAMPs) to provoke immunogenic cancer cell death (ICD) that, in turn, activates cells of the innate immune system to promote adaptive antitumor immunity. The pivotal role of the immune system in cancer treatment, in general, is highlighted by many clinical trials and success stories on using checkpoint immunotherapy. Hence, the potential of plasma treatment to induce ICD in tumor cells to promote immunity targeting cancer lesions systemically is also discussed.

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Abstract 4510: Real-time imaging of tumor cells after exposure to NDC-1308 identifies the temporal order of cellular events leading to cancer cell death

10.1158/1538-7445.am2011-4510 ◽

2011 ◽

Author(s):

James G. Yarger ◽

Michael Bittner ◽

Edward Smith ◽

Steven Nye

Keyword(s):

Cell Death ◽

Real Time ◽

Tumor Cells ◽

Cancer Cell ◽

Temporal Order ◽

Real Time Imaging ◽

Cancer Cell Death ◽

Cellular Events

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Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1212802109 ◽

2012 ◽

Vol 109 (38) ◽

pp. 15115-15120 ◽

Cited By ~ 137

Author(s):

Drew J. Adams ◽

Mingji Dai ◽

Giovanni Pellegrino ◽

Bridget K. Wagner ◽

Andrew M. Stern ◽

...

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Cancer Cell ◽

Mechanism Of Action ◽

Cell Types ◽

Structural Modifications ◽

Cancer Cell Death ◽

Nontransformed Cell

Piperlongumine is a naturally occurring small molecule recently identified to be toxic selectively to cancer cells in vitro and in vivo. This compound was found to elevate cellular levels of reactive oxygen species (ROS) selectively in cancer cell lines. The synthesis of 80 piperlongumine analogs has revealed structural modifications that retain, enhance, and ablate key piperlongumine-associated effects on cells, including elevation of ROS, cancer cell death, and selectivity for cancer cells over nontransformed cell types. Structure/activity relationships suggest that the electrophilicity of the C2-C3 olefin is critical for the observed effects on cells. Furthermore, we show that analogs lacking a reactive C7-C8 olefin can elevate ROS to levels observed with piperlongumine but show markedly reduced cell death, suggesting that ROS-independent mechanisms, including cellular cross-linking events, may also contribute to piperlongumine’s induction of apoptosis. In particular, we have identified irreversible protein glutathionylation as a process associated with cellular toxicity. We propose a mechanism of action for piperlongumine that may be relevant to other small molecules having two sites of reactivity, one with greater and the other with lesser electrophilicity.

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