<p>Mitochondrial Stress–Mediated Targeting of Quiescent Cancer Stem Cells in Oral Squamous Cell Carcinoma</p>

Abstract

Introduction: Despite improved therapeutics in oral squamous cell carcinoma (OSCC), tumor cells that are either quiescent and/or endowed with stem cell-like attributes usually survive treatment and recreate tumor load at relapse. Through this study, we aimed strategically to eliminate these stem cell-like cancer cells using a combination drug approach. Methods: Primary cultures from 15 well-moderately differentiated OSCC were established, and the existence of cancer cells with stem cell-like characteristics using five cancer stem cell (CSC) specific markers -CD44, CD133, CD147, C166, SOX2 and spheroid assay was ascertained. Next, we assessed quiescence in CSCs under normal and growth factor-deprived conditions using Ki67. Among several gene signatures regulating quiescent cellular state, we evaluated the effect of inhibiting Dyrk1b in combination with topoisomerase II and histone deacetylase inhibitors in targeting quiescent CSCs. Multiple drug-effect analysis was carried out with CompuSyn software to determine combination-index values. Results: We observed that CD44 + CD133 + showed the highest level of SOX2 expression. CSCs showed varying degrees of quiescence, and inhibition of Dyrk1b decreased quiescence and sensitized CSCs to apoptosis. In the drug-combination study, Dyrk1b inhibitor was combined with topoisomerase II and histone deacetylase inhibitors to target quiescent CSCs. In combination, a synergistic effect was seen even at a 16-fold lower dose than IC 50 . Furthermore, combined treatment decreased glutathione levels and increased ROS and mitochondrial stress, leading to increased DNA damage and cytochrome c in CSCs. Conclusion:We report marker-based identification of CSC subpopulations and synergy of Dyrk1b inhibitor with topoisomerase II and HDAC inhibitors in primary OSCC. The results provide a new therapeutic strategy to minimize quiescence and target oral CSCs simultaneously.

Overexpression of miR-651-5p inhibits ultraviolet radiation-induced malignant biological behaviors of sebaceous gland carcinoma cells by targeting ZEB2

“…Primary SGC cells were isolated from SGC tissues as described in a previous report ( 30 ). Fresh SGC tissues were placed in a culture dish containing phosphate-buffered saline (PBS; #10010023; Gibco; Thermo Fisher Scientific, Inc., USA).…”

Targeting DYRK1A/B kinases to modulate p21‐cyclin D1‐p27 signalling and induce anti‐tumour activity in a model of human glioblastoma

“…DYRK1A and DYRK1B have been demonstrated to play a role controlling the entry into senescence in a range of human cancer types including pancreatic, 32 , 33 , 34 colon, 10 ovarian 35 , 36 and squamous cell 37 carcinomas and GIST. 11 The mechanism(s) for this appear to be via the regulation of cyclin D1 and p27 stability, as well as control of the DREAM complex via LIN52.…”

“…This ubiquitination mediates DYRK1A translocation to vesicle membranes where it can phosphorylate Sprouty 2 resulting in inhibition of EGFR degradation 31. Silencing of DYRK1A or TRAF2 increases EGFR degradation and inhibition of the growth of glioma cells.DYRK1A and DYRK1B have been demonstrated to play a role controlling the entry into senescence in a range of human cancer types including pancreatic,[32][33][34] colon, 10 ovarian35,36 and squamous cell37 carcinomas and GIST.11 The mechanism(s) for this appear to be via the regulation of cyclin D1 and p27 stability, as well as control of the DREAM complex via LIN52. Inhibition of DYRK1A/B drives tumour cells out of quiescence (G0) and back into the cell cycle.…”

Roles of Mitochondria in Oral Squamous Cell Carcinoma Therapy: Friend or Foe?

“…Similarly, manoalide can cause the overexpression of cleaved caspase-3, γH2AX and 8-oxo-2′deoxyguanosine, which leads to antiproliferative effects in OSCC resulting from oxidative stress, including mtROS [ 94 ]. Moreover, DNA damage and apoptosis induced by improved mtROS were also observed in the CSCs of OSCC [ 95 ].…”