Ca²⁺ is pivotal intracellular messenger that coordinates multiple cell functions such as fertilization, growth, differentiation, and viability. Intracellular Ca²⁺ signaling is regulated by both extracellular Ca²⁺ entry and Ca²⁺ release from intracellular stores. Apart from working as the cellular recycling center, the lysosome has been increasingly recognized as a significant intracellular Ca²⁺ store that provides Ca²⁺ to regulate many cellular processes. The lysosome also talks to other organelles by releasing and taking up Ca²⁺. In lysosomal Ca²⁺-dependent processes, autophagy is particularly important, because it has been implicated in many human diseases including cancer. This review will discuss the major components of lysosomal Ca²⁺ stores and their roles in autophagy and human cancer progression.

Overlap in morphologic features between malignant and benign myogenic tumors, such as leiomyosarcoma (LMS) vs. leiomyoma as well as rhabdomyosarcoma (RMS) vs. rhabdomyoma, often makes differential diagnosis difficult and challenging. Here the expressions of Enhancer of Zeste Homolog 2 (EZH2), Suppressor of Zeste 12 (SUZ12), retinoblastoma protein associated protein 46 (RbAp46), Embryonic Ectoderm Development (EED) and ki-67 protein were detected by immunohistochemistry to evaluate their values in differential diagnosis. The expression of EZH2 mRNA was investigated by analyzing the Gene Expression Omnibus Datasets. The results demonstrated that EZH2 protein was detected in 81.25% (26/32) of LMS and 70.58% (36/51) of RMS, whereas none of leiomyoma (n = 16), rhabdomyoma (n = 15) and normal tissues (n = 31) showed positive immunostaining (p < 0.05). EZH2 protein was found to have a sensitivity of 91.30% and specificity of 100% in distinguishing well-differentiated LMS from cellular leiomyoma, and a sensitivity of 92.86% and specificity of 100% in distinguishing well-differentiated embryonal rhabdomyosarcoma (ERMS) from fetal rhabdomyoma. Besides, the expression of EZH2 mRNA was higher in LMS and RMS than in benign tumors (p < 0.05). The expressions of SUZ12 and RbAp46 protein were higher in RMS than in rhabdomyoma (p < 0.05). Conclusively, the high expression of EZH2 is a promising marker in distinguishing well–differentiated LMS from cellular leiomyoma, or well–differentiated ERMS from fetal rhabdomyoma, and the upregulation of EZH2 protein expression may occur at transcriptional level.

SLC17A9 (solute carrier family 17 member 9) functions as an ATP transporter in lysosomes as well as other secretory vesicles. SLC17A9 inhibition or silence leads to cell death. However, the molecular mechanisms causing cell death are unclear. In this study, we report that cell death induced by SLC17A9 deficiency is rescued by the transcription factor EB (TFEB), a master gene for lysosomal protein expression, suggesting that SLC17A9 deficiency may be the main cause of lysosome dysfunction, subsequently leading to cell death. Interestingly, Cathepsin D, a lysosomal aspartic protease, is inhibited by SLC17A9 deficiency. Heterologous expression of Cathepsin D successfully rescues lysosomal dysfunction and cell death induced by SLC17A9 deficiency. On the other hand, the activity of Cathepsin B, a lysosomal cysteine protease, is not altered by SLC17A9 deficiency, and Cathepsin B overexpression does not rescue lysosomal dysfunction and cell death induced by SLC17A9 deficiency. Our data suggest that lysosomal ATP and SLC17A9 play critical roles in lysosomal function and cell viability by regulating Cathepsin D activity.

Lysozyme-like proteins (LYZLs) belong to the c-type lysozyme/α-lactalbumin family and are selectively expressed in the mammalian male reproductive tract. Two members, human sperm lysozyme-like protein (SLLP) -1 and mouse LYZL4, have been reported to contribute to fertilization but show no bacteriolytic activity. Here, we focused on the possible contribution of LYZL6 to immunity and fertilization. In humans, LYZL6 was selectively expressed by the testis and epididymis and became concentrated on spermatozoa. Native LYZL6 isolated from sperm extracts exhibited bacteriolytic activity against Micrococcus lysodeikticus. Recombinant LYZL6 (rLYZL6) reached its peak activity at pH 5.6 and 15 mM of Na⁺, and could inhibit the growth of Gram-positive, but not Gram-negative bacteria. Nevertheless, the bacteriolytic activity of rLYZL6 proved to be much lower than that of human lysozyme under physiological conditions. Immunodetection with a specific antiserum localized the LYZL6 protein on the postacrosomal membrane of mature spermatozoa. Immunoneutralization of LYZL6 significantly decreased the numbers of human spermatozoa fused with zona-free hamster eggs in a dose-dependent manner in vitro. Thus, we report here for the first time that LYZL6, an acidic, bacteriolytic and human sperm-related protein, is likely important for fertilization but not for the innate immunity of the male reproductive tract.