TY - JOUR
T1 - DOC2B is a negative regulator of Wnt/β-catenin signaling pathway in cervical cancer
AU - Adiga, Divya
AU - Bhat, Samatha
AU - Chakrabarty, Sanjiban
AU - Kabekkodu, Shama Prasada
N1 - Funding Information:
We acknowledge Dr. TMA Pai Structured Ph.D. fellowship program of MAHE, and a senior research fellowship from ICMR (Reference ID- 2019/4115/CMB/BMS ), Government of India for financial assistance. All the authors thank Manipal Academy of Higher Education, Manipal, Technology Information Forecasting and Assessment Council (TIFAC)-Core in Pharmacogenomics at MAHE, Manipal, Fund for Improvement of S&T Infrastructure (FIST), and Karnataka Fund for Infrastructure Strengthening in Science and Technology (K-FIST), Government of Karnataka, and Builder Grant, Department of Biotechnology, Government of India.
Publisher Copyright:
© 2022 Elsevier Ltd
PY - 2022/6
Y1 - 2022/6
N2 - DOC2B is a ubiquitously expressed isoform of the double C-2 protein family that requires Ca2+ for most of its physiological functions. Initial findings have indicated that DOC2B participates in exocytosis, vesicular transport, insulin secretion and regulation, glucose homeostasis, and neurotransmitter release. Aberrant expression of DOC2B has been reported in diabetes, leukemia, and cervical cancer (CC). Our earlier studies have demonstrated the inhibitory effects of DOC2B on CC cell proliferation, migration, invasion, and EMT and suggested the possible role of DOC2B in Wnt signaling inhibition. However, the association between DOC2B downregulation and Wnt/β-catenin signaling activation and the underlying molecular mechanism remain elusive. Herein, we found that DOC2B inhibited Wnt/β-catenin pathway by enhancing the expression of the components of the CTNNB1 destruction complex and by fostering proteasomal degradation of CTNNB1. The translocation of CTNNB1 to the nucleus and its interaction with TCF/LEF family transcription factors was perturbed in the presence of DOC2B in a GSK3β independent manner. Further, we have identified DKK1 as one of the upregulated genes in the presence of DOC2B. DKK1 inhibition in DOC2B expressing cells by WAY262611 reactivated Wnt/β-catenin signaling, relieved DOC2B induced senescence, and alleviated the inhibitory effects of DOC2B on the aforementioned malignant behaviors. We have provided evidence for DOC2B-DKK1-senescence-Wnt/β-catenin-EMT signaling crosstalk to have tumor growth regulatory functions in CC. Thus, targeting DOC2B-DKK1-senescence-Wnt/β-catenin-EMT signaling crosstalk via activation of DOC2B may offer a novel approach to restraint malignant behaviors in CC.
AB - DOC2B is a ubiquitously expressed isoform of the double C-2 protein family that requires Ca2+ for most of its physiological functions. Initial findings have indicated that DOC2B participates in exocytosis, vesicular transport, insulin secretion and regulation, glucose homeostasis, and neurotransmitter release. Aberrant expression of DOC2B has been reported in diabetes, leukemia, and cervical cancer (CC). Our earlier studies have demonstrated the inhibitory effects of DOC2B on CC cell proliferation, migration, invasion, and EMT and suggested the possible role of DOC2B in Wnt signaling inhibition. However, the association between DOC2B downregulation and Wnt/β-catenin signaling activation and the underlying molecular mechanism remain elusive. Herein, we found that DOC2B inhibited Wnt/β-catenin pathway by enhancing the expression of the components of the CTNNB1 destruction complex and by fostering proteasomal degradation of CTNNB1. The translocation of CTNNB1 to the nucleus and its interaction with TCF/LEF family transcription factors was perturbed in the presence of DOC2B in a GSK3β independent manner. Further, we have identified DKK1 as one of the upregulated genes in the presence of DOC2B. DKK1 inhibition in DOC2B expressing cells by WAY262611 reactivated Wnt/β-catenin signaling, relieved DOC2B induced senescence, and alleviated the inhibitory effects of DOC2B on the aforementioned malignant behaviors. We have provided evidence for DOC2B-DKK1-senescence-Wnt/β-catenin-EMT signaling crosstalk to have tumor growth regulatory functions in CC. Thus, targeting DOC2B-DKK1-senescence-Wnt/β-catenin-EMT signaling crosstalk via activation of DOC2B may offer a novel approach to restraint malignant behaviors in CC.
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U2 - 10.1016/j.phrs.2022.106239
DO - 10.1016/j.phrs.2022.106239
M3 - Article
C2 - 35500882
AN - SCOPUS:85129700945
SN - 1043-6618
VL - 180
SP - 106239
JO - Pharmacological Research
JF - Pharmacological Research
M1 - 106239
ER -
