RhoA regulates resistance to irinotecan by regulating membrane transporter and apoptosis signaling in colorectal cancer

Huang, Ruihua; Zhang, Mengyi; Chong, Zhao Zhong; Meng, Qingcai; Ma, Xiaojing; Tang, Qiulin; Bi, Feng; Liu, Ming

doi:10.18632/oncotarget.13548

Cited by 16 publications

(9 citation statements)

References 28 publications

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“…S4B-S4E). RhoA has been previously shown to regulate MDR1-mediated resistance to irinotecan and doxorubicin in colon cancer cells (43,44). Our findings suggest that GPR56 regulation of drug resistance is RhoA-mediated, yet the cognate ligand and signaling mechanism downstream of RhoA is unclear.…”

Section: Discussionmentioning

confidence: 71%

GPR56 Drives Colorectal Tumor Growth and Promotes Drug Resistance through Upregulation of MDR1 Expression via a RhoA-Mediated Mechanism

Zhang

Chatterjee

Godoy

et al. 2019

Molecular Cancer Research

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Drug resistance continues to be a major obstacle of effective therapy for colorectal cancer, leading to tumor relapse or treatment failure. Cancer stem cells (CSC) or tumor-initiating cells are a subpopulation of tumor cells which retain the capacity for self-renewal and are suggested to be implicated in drug resistance. LGR5 is highly expressed in colorectal cancer and marks CSCs that drive tumor growth and metastasis. LGR5( þ ) CSCs cells were shown to interconvert with more drug-resistant LGR5( À ) cancer cells, and treatment with LGR5-targeted antibody-drug conjugates (ADC) eliminated LGR5( þ ) tumors, yet a fraction of LGR5( À ) tumors eventually recurred. Therefore, it is important to identify mechanisms associated with CSC plasticity and drug resistance in order to develop curative therapies. Here, we show that loss of LGR5 in colon cancer cells enhanced resistance to irinotecan and 5-fluorouracil and increased expression of adhesion G-protein-coupled receptor, GPR56. GPR56 expression was significantly higher in primary colon tumors versus matched normal tissues and correlated with poor survival outcome. GPR56 enhanced drug resistance through upregulation of MDR1 levels via a RhoA-mediated signaling mechanism. Loss of GPR56 led to suppression of tumor growth and increased sensitivity of cancer cells to chemotherapy and monomethyl auristatin E-linked anti-LGR5 ADCs, by reducing MDR1 levels. These findings suggest that upregulation of GPR56 may be a mechanism associated with CSC plasticity by which LGR5( À ) cancer cells acquire a more drug-resistant phenotype.Implications: Our findings suggest that targeting GPR56 may provide a new strategy for the treatment of colorectal cancer and combatting drug resistance.

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Section: Discussionmentioning

confidence: 71%

GPR56 Drives Colorectal Tumor Growth and Promotes Drug Resistance through Upregulation of MDR1 Expression via a RhoA-Mediated Mechanism

Zhang

Chatterjee

Godoy

et al. 2019

Molecular Cancer Research

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“…11 GPR56 promotes drug resistance of colorectal tumor by up-regulating MDR1 expression via a RhoA-mediated mechanism. 31 MRP1 is multidrug resistance-associated protein, and BCRP is breast cancer resistance protein. Therefore, we presumed that ANLN knockdown may inhibit the expression of MDR1 and BCRP by repressing RhoA.…”

Section: Discussionmentioning

confidence: 99%

<p>ANLN Directly Interacts with RhoA to Promote Doxorubicin Resistance in Breast Cancer Cells</p>

Wang

Xiang

Huang

et al. 2020

CMAR

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Background: Chemotherapy resistance is the leading cause of cancer treatment failure. This research was conducted to explore a potential link between actin-binding protein anillin (ANLN) and doxorubicin resistance in breast cancer. Materials and Methods: We compared ANLN expression and 50% inhibition concentration (IC50) of doxorubicin in human breast cancer cells (MDA-MB-231) and human breast cancer cells with doxorubicin resistance (MDA-MB-231/ADM). Co-immunoprecipitation was used to investigate the interaction between ANLN and RhoA. The cell viability, apoptosis, gene and protein expression were estimated by MTT, flow cytometry, quantitative real-time PCR and western blot. Results: The doxorubicin resistance in MDA-MB-231/ADM cells (IC50 = 19.40 ± 1.16 μg/ mL) was significantly higher than that in MDA-MB-231 cells (IC50 = 1.65 ± 0.23 μg/mL). ANLN was up-regulated in MDA-MB-231/ADM cells compared to MDA-MB-231 cells. Furthermore, ANLN overexpression promoted cell viability and inhibited apoptosis of MDA-MB-231 cells. The gene and protein expression of multidrug resistance (MDR1) and cancer resistance protein (BCRP) were enhanced by ANLN overexpression in MDA-MB-231 cells. ANLN silencing suppressed cell viability and the expression of MDR1 and BCRP and facilitated apoptosis in MDA-MB-231/ADM cells. Moreover, ANLN promoted RhoA activation by interacting with RhoA. ANLN up-regulation enhanced cell viability and the expression of MDR1 and BCRP and decreased apoptosis of MDA-MB-231 cells. The influence conferred by ANLN overexpression was effectively abolished by C3 transferase. Conclusion: This work revealed that ANLN promoted doxorubicin resistance in breast cancer cells by activating RhoA. Thus, our study suggests a novel target for breast cancer treatment.

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“…Analyzing the gene profiles of 137 colorectal tumor samples in humans, it was indicated that RHOA is one of the most altered gene among RAS homologues, and RHOA expression shows a positive correlation with survival time [ 87 ]. Beside this, RHOA was found to be upregulated in chemoresistant-CRC, playing a role in the expression of cell membrane transporter and apoptosis in colon cancer, contributing to chemotherapeutic resistance in colorectal cancer patients [ 88 ].…”

Section: Rhoa (Ras Homology Family Member A)mentioning

confidence: 99%

Rho GTPases as Key Molecular Players within Intestinal Mucosa and GI Diseases

Pradhan

Ngo

Martínez-Sánchez

et al. 2021

Cells

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Rho proteins operate as key regulators of the cytoskeleton, cell morphology and trafficking. Acting as molecular switches, the function of Rho GTPases is determined by guanosine triphosphate (GTP)/guanosine diphosphate (GDP) exchange and their lipidation via prenylation, allowing their binding to cellular membranes and the interaction with downstream effector proteins in close proximity to the membrane. A plethora of in vitro studies demonstrate the indispensable function of Rho proteins for cytoskeleton dynamics within different cell types. However, only in the last decades we have got access to genetically modified mouse models to decipher the intricate regulation between members of the Rho family within specific cell types in the complex in vivo situation. Translationally, alterations of the expression and/or function of Rho GTPases have been associated with several pathological conditions, such as inflammation and cancer. In the context of the GI tract, the continuous crosstalk between the host and the intestinal microbiota requires a tight regulation of the complex interaction between cellular components within the intestinal tissue. Recent studies demonstrate that Rho GTPases play important roles for the maintenance of tissue homeostasis in the gut. We will summarize the current knowledge on Rho protein function within individual cell types in the intestinal mucosa in vivo, with special focus on intestinal epithelial cells and T cells.

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RhoA regulates resistance to irinotecan by regulating membrane transporter and apoptosis signaling in colorectal cancer

Cited by 16 publications

References 28 publications

GPR56 Drives Colorectal Tumor Growth and Promotes Drug Resistance through Upregulation of MDR1 Expression via a RhoA-Mediated Mechanism

GPR56 Drives Colorectal Tumor Growth and Promotes Drug Resistance through Upregulation of MDR1 Expression via a RhoA-Mediated Mechanism

<p>ANLN Directly Interacts with RhoA to Promote Doxorubicin Resistance in Breast Cancer Cells</p>

Rho GTPases as Key Molecular Players within Intestinal Mucosa and GI Diseases

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