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Endolysosomal Ca2+ Signaling in Cancer: The Role of TPC2, From Tumorigenesis to Metastasis.

ABSTRACT: Ca2+ homeostasis is dysregulated in cancer cells and affects processes such as tumorigenesis, angiogenesis, autophagy, progression, and metastasis. Emerging evidence has suggested that endolysosomal cation channels sustain several cancer hallmarks involving proliferation, metastasis, and angiogenesis. Here, we investigate the role of TPC1-2, TRPML1-3, and P2×4 in cancer, with a particular focus on the role of TPC2 in cancer development, melanoma, and other cancer types as well as its endogenous and exogenous modulators. It has become evident that TPC2 plays a role in cancer; however, the precise mechanisms underlying its exact role remain elusive. TPC2 is a potential candidate for cancer biomarkers and a druggable target for future cancer therapy.

SUBMITTER: Alharbi AF

PROVIDER: S-EPMC6904370 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Endolysosomal Ca<sup>2+</sup> Signaling in Cancer: The Role of TPC2, From Tumorigenesis to Metastasis.

Alharbi Abeer F AF Parrington John J

Frontiers in cell and developmental biology 20191204

Ca<sup>2+</sup> homeostasis is dysregulated in cancer cells and affects processes such as tumorigenesis, angiogenesis, autophagy, progression, and metastasis. Emerging evidence has suggested that endolysosomal cation channels sustain several cancer hallmarks involving proliferation, metastasis, and angiogenesis. Here, we investigate the role of TPC1-2, TRPML1-3, and P2×4 in cancer, with a particular focus on the role of TPC2 in cancer development, melanoma, and other cancer types as well as its ...[more]

PMID: 31867325

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Project description:Recent studies have implicated important roles for endolysosomal ion channels in cancer biology. We used UK Biobank data to characterise the relationships between genetic variants in two genes coding for endolysosomal ion channels-i.e. TPCN2 and P2RX4-and cancer in terms of the definition of tumour types, susceptibility, and prognosis. We investigated these relationships at both global and local levels with regard to specific types of cancer, including malignant neoplasms of the brain, breast, bronchus, lung, colon, lymphoid and haematopoietic systems, skin, ovary, prostate, rectum, thyroid gland, lip, oral cavity, pharynx, and urinary tract. Apart from rs3829241 (p value < 0.05), all the genetic variants were in Hardy-Weinberg equilibrium. We included 468,436 subjects in the analysis and stratified them into two major cohorts: cancer-free controls (385,253) and cancer cases (83,183). For the first time, we report novel associations between genetic variants of TPCN2 and P2RX4 and cancer/cancer subtypes in the UK Biobank's population. Genotype GG in TPCN2 rs3750965 was significantly associated with a decreased risk of cancer and an increased risk of lip, oral cavity, and pharynx cancer and cancer recurrence in patients with prostate cancer, and genotypes GA/GG were associated with a significantly lower risk of developing various malignant neoplasms (involving melanoma, prostate, mesothelial, and soft tissues). rs35264875:TA was associated with a high risk of cancer at the global level, with subtypes of cancer at the local level (including breast, colon, prostate, and stated or presumed primary cancer of lymphoid, haematopoietic, and related tissue), and with a significantly low risk of cancer metastasis. rs72932540:GA was associated with a higher incidence of cancer/cancer subtypes (including breast, melanoma, and rectal cancer), and genotypes GA/GG were associated with an increased risk of prostate cancer. The P2RX4 rs25644 allele GG was associated with a high risk of prostate cancer, whereas it was associated with a low risk of cancer recurrence in patients with prostate cancer. Genotypes GA/GG in rs28360472 were associated with an increased risk of breast, mesothelial, and soft tissue cancers but with a decreased risk of colon cancer. We also provide insights into the pathophysiological contributions made by these significant polymorphisms to cancer/cancer subtypes and their effects on expression or channel activity. Further investigations of these genetic variants could help identify novel cancer biomarkers and facilitate the development of new diagnostic and therapeutic strategies. This would constitute a further step towards personalised cancer care.

Project description:IntroductionTransmembrane protein 16A (TMEM16A) is a Ca2+-activated chloride channel that plays a role in cancer cell proliferation, migration, invasion, and metastasis. However, whether TMEM16A contributes to breast cancer metastasis remains unknown.ObjectiveIn this study, we investigated whether TMEM16A channel activation by ROCK1/moesin promotes breast cancer metastasis.MethodsWound healing assays and transwell migration and invasion assays were performed to study the migration and invasion of MCF-7 and T47D breast cancer cells. Western blotting was performed to evaluate the protein expression, and whole-cell patch clamp recordings were used to record TMEM16A Cl- currents. A mouse model of breast cancer lung metastasis was generated by injecting MCF-7 cells via the tail vein. Metastatic nodules in the lung were assessed by hematoxylin and eosin staining. Lymph node metastasis, overall survival, and metastasis-free survival of breast cancer patients were assessed using immunohistochemistry and The Cancer Genome Atlas dataset.ResultsTMEM16A activation promoted breast cancer cell migration and invasion in vitro as well as breast cancer metastasis in mice. Patients with breast cancer who had higher TMEM16A levels showed greater lymph node metastasis and shorter survival. Mechanistically, TMEM16A promoted migration and invasion by activating EGFR/STAT3/ROCK1 signaling, and the role of the TMEM16A channel activity was important in this respect. ROCK1 activation by RhoA enhanced the TMEM16A channel activity via the phosphorylation of moesin at T558. The cooperative action of TMEM16A and ROCK1 was supported through clinical findings indicating that breast cancer patients with high levels of TMEM16A/ROCK1 expression showed greater lymph node metastasis and poor survival.ConclusionOur findings revealed a novel mechanism underlying TMEM16A-mediated breast cancer metastasis, in which ROCK1 increased TMEM16A channel activity via moesin phosphorylation and the increase in TMEM16A channel activities promoted cell migration and invasion. TMEM16A inhibition may be a novel strategy for treating breast cancer metastasis.

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Dataset Information

Endolysosomal Ca2+ Signaling in Cancer: The Role of TPC2, From Tumorigenesis to Metastasis.

Publications

Endolysosomal Ca<sup>2+</sup> Signaling in Cancer: The Role of TPC2, From Tumorigenesis to Metastasis.

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